William Wilkins was born in Carlisle, Pennsylvania on December 20, 1779, one of ten children of Captain John Wilkins, an influential Presbyterian land-owner who later went into business in Pittsburgh, and his wife Catherine Rowan. His sister, Nancy Wilkins, married Ebenezer Denny, the first mayor of Pittsburgh, and Hamar Denny, who also attended the local Dickinson College, was his nephew. William returned to his birthplace to enter Dickinson's class of 1802 but did not graduate and instead studied the law under David Watts.
He was admitted to the Pittsburgh Bar in December 1801 and began a private practice. He later entered manufacturing and banking, becoming the first president of the Bank of Pittsburgh in 1814. He was elected to the state house as a Federalist in 1821 but resigned soon after to become the presiding judge of the fifth judicial district of Pennsylvania. In 1824, he became a federal judge and in 1831 was selected to the United States Senate as a Jacksonian Democrat. He served until 1834 when he was named Minister to Russia after challenging Van Buren's bid for the vice presidency. When he returned, he served briefly in the House until President Tyler appointed him to be his Secretary of War in February 1844, a post in which he advocated western territorial expansion. When he left this position in 1845, it was his last involvement with politics other than a short term as a Democratic state representative in between 1855 and 1857.
He retired to a large estate near Pittsburgh, known as "Homewood," where he built an impressive Greek style mansion. Though still a Democrat, he vigorously advocated the Union cause when the Civil War broke out, taking the ceremonial position of major general in the Pennsylvania Home Guard in 1862.
He married Catherine Holmes who died after
only one year in 1816. He then married Mathilda Dallas in 1818, with
whom he had seven children. William Wilkins died at "Homewood" on
June 23, 1865.