Born in Durham, North Carolina in 1928 of Greek-American ancestry, Galifianakis attended local public schools and then Duke University, earning a bachelor's degree in 1951 and a law degree in 1953. After serving in the United States Marine Corps Reserve from October 1953 to April 1956, he was admitted to the bar and practiced law in Durham. In 1960, he became an assistant professor of business law at Duke and was elected to the North Carolina General Assembly in 1961. Galifianakis left both positions when elected to the United States Congress in 1966. He served three terms (January 3, 1967 - January 3, 1973). He did not stand for re-election to the House in 1972 but unsuccessfully ran against Jesse Helms for an open seat in the United States Senate. After leaving Congress, he resumed his law practice, and currently lives in Durham, North Carolina.
Since 1997 his nephew, also named Nick Galifianakis, has been drawing the satirical cartoons that accompany the advice column "Tell Me About It" in the Washington Post tri-weekly, which is written by his ex wife, Carolyn Hax.