Pryor is a native of Camden in Ouachita County in south Arkansas, and a lawyer who graduated from the University of Arkansas in Fayetteville. He served prior to 1966 as a member of the Arkansas House of Representatives. From 1966 to 1973, he was a member of the United States House of Representatives from Arkansas' 4th congressional district. He ran unsuccessfully for the United States Senate in the 1972 Democratic primary, having been defeated by the long-term incumbent John McClellan.
In 1974, he defeated former Governor Orval E. Faubus for the Democratic gubernatorial nomination and then handily beat the Republican Ken Coon in the general election for the right to succeed Governor Dale Bumpers, who became U.S. senator after defeating J. William Fulbright in the Democratic primary. After four years as governor, Pryor was succeeded by Bill Clinton. In 1978, Pryor was handily elected to the U.S. Senate and reelected in 1984 and 1990. He declined to run again in 1996 and was succeeded by the Republican Tim Hutchinson, then a U.S. representative. In 2002, Hutchinson was unseated after a single term by Pryor's son, Mark Pryor, who still holds the seat.
From September 2008 to February 2009, Pryor was chairman of the Arkansas Democratic Party.