Born in Glastonbury, Connecticut, Welles intended, as a young man, to become a lawyer, but soon shifted to journalism and became the founder and editor of the Hartford Times in 1826. Quickly thereafter he became a member of the Connecticut state legislature as a Democrat. His support of the Democratic Party earned him several political offices later in his career, including State Controller of Public Accounts in 1835, Postmaster of Hartford (1836-41), and Chief of the Bureau of Provisions and Clothing for the Navy (1846-49).
Welles shifted allegiance in 1854 to the newly-founded Republican Party, and founded a newspaper in 1856 (the Hartford Evening Press) that would espouse Republican ideals for decades thereafter. In gratitude for his support, Welles was made Secretary of the Navy by Abraham Lincoln, the first Republican president, in 1861. When war broke out between the Union and the Confederacy, Welles's department was responsible for the difficult task of blockading the entire southern coastline of the United States (which stretched to over 3,500 miles), in order to weaken the Confederacy economically (a strategy known as the Anaconda Plan). While the blockade was never completely effective, its economic impact on the South proved large enough to contribute significantly towards ending the war.
Despite his successes, Welles was never at ease in the United States Cabinet. His anti-English sentiments caused him to clash with William Seward, Secretary of State, and Welles's conservative stances led to arguments with Salmon P. Chase and Edwin Stanton, the Secretaries of the Treasury and of War, respectively. Welles ultimately left the Cabinet in 1869, having returned to the Democratic Party in 1868: his criticisms of Andrew Johnson and the federal policies of reconstruction had given fuel to his leaving.
After leaving politics, Welles returned to writing, authoring several books before his death, including Lincoln and Seward in 1874. His diary (posthumously published in 1911) remains a unique and fascinating insight into the personalities and problems of the men who coordinated the Northern efforts in the Civil War. Welles died in 1878 in Hartford, Connecticut.