Sayers first gained national attention as a two-time All-American (1963–64) at the University of Kansas in Lawrence. He was drafted by the Chicago Bears in 1965, and in his first season he amassed 2,272 combined rushing, receiving, and kick-return yards, as well as 22 touchdowns, then a record for a rookie. That year, in a game against the San Francisco 49ers, he tied an NFL record by scoring six touchdowns in a single game. Not surprisingly, he was named Rookie of the Year in 1965. He twice led the league in rushing (1966, 1969), was named All-NFL five years in a row (1965–69), and has the best career kickoff-return average in the NFL.

A series of significant knee injuries forced Sayers to retire at age 29 before the 1972 NFL season. He later served as assistant athletic director at the University of Kansas (1972–76) and as athletic director at Southern Illinois University, Carbondale (1976–81). In 1984 Sayers founded a successful computer supplies business. His close friendship with fellow Bears halfback Brian Piccolo, who died of cancer in 1970, was depicted in the 1971 television movie Brian's Song. Sayers cowrote two autobiographies, I Am Third (with Al Silverman; 1970) and Sayers: My Life and Times (with Fred Mitchell; 2007).