Samuel Andrew Witherspoon (May 4, 1855 – November 24, 1915) was a U.S. Representative from Mississippi.

Born near Columbus, Mississippi, Witherspoon attended the public schools.

He graduated from the University of Mississippi at Oxford in 1876 with a degree in law.

He was admitted to the bar in 1879 and commenced practice in Meridian, Mississippi, the same year.

Witherspoon was elected as a Democrat to the Sixty-second, Sixty-third, and Sixty-fourth Congresses and served from March 4, 1911, until his death in Meridian, Mississippi, November 24, 1915.