Isaac Donnom Witherspoon (December 3, 1803 - July 30, 1858) was a politician in South Carolina.
He served in the state house and then the state senate. He succeeded William K. Clowney as lieutenant governor and served from December 1842 until December 1844. He was succeeded by John Fulton Ervin.
Isaac Witherspoon died of a stroke in 1858, aged 54.