Appleton married Sarah Newcomb Allen, sister of his then law partner and future congressman, Elisha Hunt Allen, in 1834. He had five children, John, Frederic, Sarah, Henry, and Edward. His oldest, also named John, was a Brigadier General in the Union Army who led a significant detachment of men at the Siege of Port Hudson. Sarah died on 12 August 1874. Appleton remarried under two years later to Annie V. Greeley on 30 March 1876. Annie and John had no known children. Appleton was a member of the Unitarian Church.