William Henry Seward (he went by Henry in close circles) was born May 16, 1801 to Samuel Sweezey Seward and Mary Seward (née Jennings) in Florida, New York. He was the third of five children who lived to adulthood. His siblings were Benjamin Jennings Seward, Edwin Polydore Seward, Louisa Cornelia Canfield (née Seward), and George Washington Seward.

Henry graduated from Union College in Schenectady, New York in 1820, studied law, and was admitted to the New York State bar in October 1822. He moved to Auburn, New York in 1823 and worked for Judge Elijah Miller. On October 20, 1824, Henry married Judge Miller's daughter, Frances Adeline Miller. They had five children, Augustus Henry Seward, Frederick William Seward, William Henry Seward Jr., Cornelia Seward (who died in infancy), and Frances Adeline Seward.

Henry was an agent for the Holland Land Company with his brother, Benjamin, from 1836 to 1838, when he bought an interest in the company. He was a New York State Senator from 1830 to 1834 and served as Governor of New York from 1839 to 1842. In 1849, he was elected as a U. S. Senator. Abraham Lincoln nominated Henry as Secretary of State in 1861, a position he held until his retirement in 1869.

On April 14, 1865, Henry and his son, Frederick, were severely injured by Lewis Powell in the same coordinated attack that killed Lincoln. Within two years of the attack, Henry's wife and daughter died. From 1870 to 1871, Henry went on a world tour with Ms. Olive Risley, whom he adopted in 1870, her sister Harriet Risley, and several others. On October 10, 1872, Henry died in his Auburn residence at 33 South Street and is buried next to his wife in Fort Hill Cemetery in Auburn.