He began his NFL career with the New York Giants by playing both offense and defense, a rarity when platoon football became popular after World War II. He made eight Pro Bowl appearances and had five trips to the NFL Championship Game. Gifford's biggest season may have been 1956, when he won the Most Valuable Player award of the NFL, and led the Giants to the NFL title over the Chicago Bears.

He lost 18 months in the prime of his career when he was laid out by a hard tackle. During a 1960 game against the Philadelphia Eagles, he was knocked out by Chuck Bednarik on a passing play, suffering a severe head injury that led him to retire from football. However, Gifford returned to the Giants in 1962, changing positions from running back to wide receiver (then known as flanker). Despite his long layoff and having to learn a new position, he became a star once again.