Peale was born in Queen Anne's County, Maryland and became an apprentice to a saddle maker when he was thirteen years old. Upon reaching majority he opened his own saddle shop; however, when his Loyalist creditors discovered he had joined the Sons of Freedom organization, they conspired to bankrupt his business.
Finding that he had a talent for painting, especially portraits, Peale studied for a time under John Hesselius and John Singleton Copley; eventually friends raised enough money for him to travel to England to take instruction from Benjamin West. Peale studied with West for two years beginning in 1767, afterward returning to America and settling in Annapolis, Maryland.
Peale's enthusiasm for the nascent national government brought him to the capital, Philadelphia, in 1776 where he painted portraits of American notables and visitors from overseas. He also raised troops for the revolution and eventually gained the rank of captain in 1777, having participated in several battles. While in the field he continued to paint, doing miniature portraits of various officers in the Continental Army, of which he would develop enlarged versions in later years. He served in the Pennsylvania state assembly in 1779-80, after which he returned to painting full-time.
Peale was quite prolific as an artist, and while he did portraits of scores of historic figures (such as John Hancock, Thomas Jefferson and Alexander Hamilton), he is probably best known for his portraits of George Washington. The first time Washington ever sat for a portrait was with Peale in 1772, and there would be six other sittings; using these seven as models Peale produced altogether close to 60 portraits of Washington.
He also had a great interest in natural history, and organized the first U.S. scientific expedition in 1801. These two major interests combined in his founding of what became the Philadelphia Museum, and was later renamed the Peale Museum. This museum was stocked with artwork supplied by Peale, as well as artifacts of natural history, such as a mastodon skeleton found on the first expedition.
Peale could accurately be described as a "renaissance man", having developed a certain level of expertise in such diverse fields as carpentry, dentistry, optometry, shoemaking and taxidermy. He also wrote several books, among which were An Essay on Building Wooden Bridges (1797) and An Epistle to a Friend on the Means of Preserving Health (1803). He taught all of his children to paint, and three of them, Rembrandt, Raphaelle and Titian Ramsay, became noted artists in their own right.