Unitas played football at St. Justin's High School (Pittsburgh), but his low weight (145 pounds 【66 kg】) caused him to be rejected for an athletic scholarship at the University of Notre Dame. He played for the University of Louisville (Kentucky), where he grew to 6 feet 1 inch (1.85 metres) and 190 pounds (86 kg). He was drafted by the NFL Pittsburgh Steelers in the ninth round in 1955 but was released before the regular season began. He worked at construction jobs and played for the semiprofessional Bloomfield Rams for $6 a game until he joined the NFL Baltimore Colts (Indianapolis Colts) in 1956. His rise to stardom from such lowly beginnings made him the quintessential rags-to-riches hero as professional football emerged as the top spectator sport in the United States in the 1960s. His legendary status was cemented by his performance in the 1958 championship game, in which he led the Colts to a 23–17 overtime victory over the New York Giants. The dramatic game, viewed by a national television audience, is regarded as a key step in the NFL's rise in popularity.

Unitas led the Colts to five league championship games (1958–59, 1964, 1968, and 1970) and to two Super Bowl games (after the 1968 and 1970 seasons). He led the league four times each in passing yards and in touchdown passes and retired with career NFL records for passing yards, touchdowns, and completions. He was traded to the NFL San Diego Chargers in 1973, his last season. He was elected to the Pro Football Hall of Fame in 1979.