Born Melanie Hamilton around 1845 in Clayton County, Georgia, USA, she and her brother Charles Hamilton are among the last members born in the cotton plantation of the relatively affluent Hamilton family. The family have always valued education and sought to provide their members with the finest available. As a result, they have gained a reputation for producing a fair number of intellectuals and several noted lawyers. For several generations they have intermarried with the like-minded Wilkes family. Unfortunately, this practice of apparent inbreeding has eventually resulted in the birth of progressively sicklier children.
Melanie's and Charles' parents die when their children are still young. The two siblings are placed under the joint guardianship of Henry Hamilton and Sarah Jane "Pittypat" Hamilton, their father's brother and sister. Neither of them is married and so they consider their nephews as their children. Henry is a lawyer and resident of Atlanta and the family fortune has been placed under his management. Pittypat is described as having the maturity of a child herself. The one actually responsible for raising the two children is Uncle Peter, an African American slave. Peter is fiercely loyal to the Hamiltons and served the orphans' father during his military service in the Mexican-American War. Though the Hamiltons are nominally his masters, Peter views them more as his charges and acts as the protector of Pittypat and her nephews throughout their lives. He is described as a brave and intelligent man who, in serving the interests of the Hamiltons, often advises his charges and on several occasions takes decisions for them. Thanks to their devoted uncles and aunt, the siblings grow to be well-educated and well-read young people, but due to their somewhat sheltered environment, they tend to be naive in social ways.
In keeping with the family tradition, on April, 1861 Melanie becomes engaged to her cousin, Ashley Wilkes. Melanie is unaware that Scarlett O'Hara intended to marry Ashley herself. For Scarlett the news is shocking. Nevertheless she is present at the engagement celebration, along with her family and most other plantation owners of the county. Melanie and Scarlett first meet at that celebration. According to her description, Melanie is a rather petite and delicate young woman with the height and weight of a child. Her most notable feature is her large black eyes. To Scarlett she seems quite shy and sweet but not particularly beautiful. However, her way of movement is described as graceful beyond her years. To Scarlett she seems more interested in discussing books than in flirting with men. While most young girls present at the celebration seek to impress the young men with their dress sense, Melanie is plainly clothed and discussing the works of William Makepeace Thackeray and Charles Dickens.
Scarlett is certain that Ashley will prefer her to Melanie. Confronting him privately she confesses her love for him. Ashley admits he is attracted to her but he is determined to marry Melanie. His main stated reason is that he believes he has more in common with Melanie than with Scarlett. Scarlett feels disappointed and hurt. In her confusion she decides to hurt Ashley in return by accepting a marriage proposal she previously turned down; a marriage proposal by Charles Hamilton. Scarlett also considers that she is taking revenge against Melanie by marrying her brother.
The wedding takes place two weeks later on April 30, 1861, but Melanie is actually pleased about the marriage as she views her new sister-in-law as a true sister. Melanie seems to take an instant liking to Scarlett and welcomes her to their family. On May 1, 1861 Melanie herself marries Ashley. Meanwhile the American Civil War is raging and Georgia is now part of the Confederate States of America. Melanie's brother has to leave two weeks after his marriage to enlist in the forces of Wade Hampton, known as "Hampton's Legion". A week later Melanie's husband follows him. In his absence Melanie accepts the invitation of Aunt Pittypat to stay with her in Atlanta. The fortunes of both women are still under the management of Uncle Henry.
In Atlanta Melanie receives two important pieces of news. Her brother died less than two months after his enlistment, having contracted and recovered from the measles but then dying of pneumonia. His share of the family fortune is inherited by Scarlett, his widow. This sad news is followed by the news of Scarlett's pregnancy. Melanie's nephew is born by the end of the year and is named Wayde Hampton Hamilton.
Throughout the year both Melanie and her aunt send Scarlett several invitations to join them. Melanie expresses an interest in getting to know her "sister" better and later in seeing her nephew. On the other hand, Scarlett is going through a state of depression. Her mother is concerned about her and finally manages to convince her to accept the invitations. Following a short visit to maternal relatives in Charleston, South Carolina, Scarlett and her son arrive in Atlanta during the first months of 1862. She is welcomed by Uncle Peter, aging but still determined to take care of his new charge. He brings her to the house of her aunt and sister-in-law.
At first feeling awkward with the thought of living under the same roof with Ashley's wife, Scarlett progressively regains her interest in life. Partly responsible for that is Melanie's interest and affection towards her, though her occasional crushing hugs are hard for Scarlett to get used to. Melanie is serving as a volunteer nurse in the local hospital. Soon Scarlett joins her. Scarlett is somewhat impressed with Melanie's ability to keep a straight face and a smile in the presence of the wounded and her willingness to help and comfort them. Even if some of the gravest wounds make her pale and even cause her to vomit privately, Melanie avoids letting others find out. Scarlett starts considering that her sister-in-law is braver than she appears. At the same time Melanie maintains correspondence with Ashley, and Scarlett is still interested in hearing of his activities.
Scarlett has come to Atlanta intending to stay for a short while and as a visitor, but soon she finds herself settled more permanently and one of Atlanta's socialites. Melanie seems content with the new situation as Scarlett proves to be a better companion than their elderly aunt. At the time Atlanta is seemingly populated mostly by women, by men too old or too young to fight, and the wounded returning from the front. However, a number of men eligible to fight still remain in the city as part of the local militia. Melanie harshly criticises their presence in the city, while more forces are needed at the front. Scarlett soon finds that, as passively as Melanie usually acts, she can become surprisingly passionate and even aggressive in support of her ideals.
By the summer of 1862 Melanie and Scarlett have been re-acquainted to a man they met during Melanie's engagement celebration: Captain Rhett Butler, at the time about 35 years old. Born to a respected family of Charleston, South Carolina, Rhett was disinherited by his father when he refused to marry according to the latter's wishes. He has worked his way up and has made his own fortune in the California gold rush of 1848-1849. He has gained wealth and success as a trader but he has a poor reputation. At the time he and his sailing ship have been smuggling supplies from the United Kingdom of Great Britain and Ireland, France and even the port of New York, New York to the Confederation. Noted for his cynicism, he observes that he has gained both in wealth and in appreciation by this practice. He seems to take an instant interest in befriending both young women and soon starts flirting with Scarlett. Though this provides a subject of gossip for the local society, Melanie seems to approve of both her friends and verbally defends their reputations.
By early 1863 Rhett has established himself as a friend of both women and a frequent visitor to their house. To Melanie he seems a bitter man in need of a woman to comfort him. On the other hand, Scarlett shares much of his cynical view towards people and their ideas. Both women find some of his ideas disturbing but still thought-provoking. In discussion with patriots and idealists who think this is a just war, Rhett tends to point that all wars seem just to the soldiers fighting them, but that the leaders and orators guiding them to war tend to place themselves behind the lines and are more interested in monetary gain than ideals. Rhett also points out that those ideals are little more than a cover for the actual financial motivation behind wars. Rhett's often stated beliefs have earned him a fair number of enemies, but Melanie and Scarlett are not among them as they also tend to question the motivations behind the war.
Generally less judgemental than most members of her social circle, Melanie is surprised when she is approached by Belle Watling, an affluent prostitute and owner of a local brothel. Belle has become well-known in the local society and respected members of it frequent her brothel, but in public she usually finds herself isolated. Intending to contribute part of her weekly earnings as charity for the local hospital, Belle has found her offer being rejected. The idea is that money from such a source would be an insult to the heroic and wounded soldiers. Instead, Melanie accepts the offer. Melanie privately explains to Scarlett, who by this point has become her closest confidante, that in the process she risks her own reputation, but she reasons that the hospital needs any help it could get and that Belle's intentions are noble in this case.
Meanwhile Ashley has been serving in the Army of Northern Virginia and has been promoted to the rank of major. Having participated in a number of victorious battles, this army is steadily advancing towards the northern states under the orders of General Robert Edward Lee. On July 1, 1863 the army is engaged in battle against the Federal near the village of Gettysburg, Pennsylvania. The battle lasts till July 3, 1863 and is known as the Battle of Gettysburg. It ends in the defeat and retreat of the Confederates. The news of the battle reach Atlanta early but both the outcome and the fates of many of the soldiers remain uncertain for some time after. Many wait to learn news of their relatives and friends. Melanie and Scarlett have a personal interest in the fate of Ashley, whom they still both love. When the first lists of casualties reaches Atlanta both are relieved not to find Ashley among them. But their relief is soon followed by grief as, not surprisingly, Melanie, Scarlett and every resident of Atlanta find many of their acquaintances to be included in the lists. And several additions to the lists follow. The battle has been the first major defeat of the Confederates and is considered to have turned the tide of the war.
On December 20, 1863 Ashley returns home. He has received a week-long leave. It is the first time Melanie and Scarlett have seen him in about two years. The weary soldier is met with the joy and affection of both women and seems to return it. Before leaving to rejoin his unit, Ashley explains to Scarlett his worries about his wife's current health and her fate in case he falls in battle. Ashley meets Scarlett with the specific request to look and care after Melanie in his absence. Scarlett is at first taken by surprise but she agrees. Scarlett accepts Melanie as her new charge and for the first time feels responsible for her sister-in-law and rival in love's health and care. Melanie is left blissfully unaware of the feelings her husband and "sister" have for each other and the latter's new responsibility towards herself.
Ashley's short visit has apparently been enough for Melanie to be three months pregnant by March, 1864. Melanie has wanted a child for some time and already acted as a second mother to her nephew Wayde. She is glad for the chance to have her own child. Melanie announces the news to Scarlett as soon as she is certain. She expects her friend to share her joy. Having lost her mother years ago, Melanie also seems to expect Scarlett to assume the role of the experienced woman advising her on her pregnancy, but instead Scarlett reacts in surprise, confusion and even anger to finding Melanie pregnant with Ashley's child. Melanie is unable to grasp the reasons for this reaction but fears that she has somehow hurt her friend. Melanie is also met with the fears of the doctor examining her. According to his examination, Melanie's hip bone seems to be too narrow to safely allow her to give birth. In any case Melanie sends a telegram to Ashley announcing the news. It is answered by a telegram from Ashley's superior officer explaining that her husband has been reported as missing in action for the last three days. Melanie finds herself believed to be a widow.
Turning to each other for comfort, Melanie and Scarlett reconcile. They spend that night crying in each other's arms while sharing Scarlett's bed. But the news of Ashley's death prove to have been premature. Another report informs the two women that efforts to recover his body have failed and that he is considered likely to have been captured by enemy forces. Anxious over her husband's uncertain fate, Melanie grows restless for some time. Even late at night Scarlett can hear Melanie pacing her bedroom back and forth, apparently suffering from insomnia. This practice gradually exhausts her health and at one point she even passes out in public, an unusual incident for her. Fortunately for Melanie, Rhett happens to be near and returns her home safely. Rhett is reasonably worried about her. Learning the reasons behind her current state, he promises to use his connections in Washington, DC to find out whether Major Wilkes has been captured or not. In exchange, Rhett askes Melanie to promise him that she will try to get some rest.
A month later Rhett announces to Melanie and Scarlett what has happened to Ashley. He has been wounded in conflict, captured, and is being held in a prisoner camp in Rock Island, Illinois. The women receive the news with mixed feelings. Their loved one is still alive but for how long is questionable. Rock Island's reputation among the Confederates is no better than that of Andersonville among the Federals and that only one quarter of the prisoners held there have ever returned home. The rest die from smallpox, pneumonia and typhus, among other diseases.