With the Colts, Tittle was named the AAFC Rookie of the Year in 1948 after leading the team to the AAFC playoffs. After back-to-back one-win seasons, the Colts franchise folded, which allowed Tittle to be drafted in the 1951 NFL Draft by the 49ers. Through ten seasons in San Francisco, he was invited to four Pro Bowls, led the league in touchdown passes in 1955, and was named the NFL Player of the Year by the United Press in 1957. A groundbreaker, Tittle was part of the 49ers' famed Million Dollar Backfield, was the first professional football player featured on the cover of Sports Illustrated, and is credited with having coined "alley-oop" as a sports term.
Considered washed-up, the 34-year-old Tittle was traded to the Giants following the 1960 season. Over the next four seasons, he won several individual awards, twice set the league single-season record for touchdown passes, and led the Giants to three straight NFL championship games. Although he was never able to deliver a championship to the team, Tittle's time in New York is regarded among the glory years of the franchise.
In his final season, Tittle was photographed bloodied and kneeling down in the end zone after a tackle by a defender left him helmetless. The photograph is considered one of the most iconic images in North American sports history. He retired as the NFL's all-time leader in passing yards, passing touchdowns, attempts, completions, and games played. Tittle was inducted into the Pro Football Hall of Fame in 1971, and his jersey number 14 is retired by the Giants.
UPI again named Tittle its first-team All-SEC quarterback in 1947. In Tittle's day of iron man football, he played on both offense and defense. While on defense during a 20–18 loss to SEC champion Ole Miss in his senior season, Tittle's belt buckle was torn off as he intercepted a pass from Charlie Conerly and broke a tackle. He ran down the sideline with one arm cradling the ball and the other holding up his pants. At the Ole Miss 20-yard line, as he attempted to stiff-arm a defender, Tittle's pants fell and he tripped and fell onto his face. The fall kept him from scoring the game-winning touchdown.
In total, during his college career Tittle set school passing records with 162 completions out of 330 attempts for 2,525 yards and 23 touchdowns. He scored seven touchdowns himself as a runner. His passing totals remained unbroken until Bert Jones surpassed them in the 1970s.