Blanda was signed by the Chicago Bears for $600 in 1949, an amount owner George Halas demanded back when he made the team. While primarily used as a quarterback and placekicker, Blanda also saw time on the defensive side of tha ball at linebacker. It would not be until 1953 that Blanda would emerge as the Bears' top signal caller, but an injury the following year effectively ended his first-string status. For the next four years, he would used mostly in a kicking capacity. Later commenting on his testy relationship with Halas, Blanda noted, "He was too cheap to even buy me a kicking shoe."

Blanda retired after the 1958 NFL season because of Halas' insistence on only using him as a kicker, but returned in 1960 upon the formation of the American Football League. He signed with the Houston Oilers as both a quarterback and kicker. He was derided by the sports media as an "NFL Reject", but he went on to lead the Oilers to the first two league titles in AFL history, and he won AFL Player of the Year honors in 1961. During that season, he had two 400-yard passing days for the Oilers: a 464-yard effort against the Buffalo Bills on October 29, with four touchdown passes (winning 28-16); and 418 yards three weeks later against the Titans of New York, this time with seven touchdown passes in a 49-13 victory. Blanda passed for 36 touchdowns that season. On 13 occasions, he connected on four or more touchdown passes during a game, and on November 1, 1964, unleashed 68 passes for Houston against the Buffalo Bills.

From 1963-1965, Blanda led the AFL in passing attempts and completions, and ranked in the top ten for attempts, completions, yards and touchdowns during seven consecutive seasons. A four-time member of the American Football League All-Star team, Blanda's already-long career seemed over when he was released by the Oilers on March 18, 1967. However, the Oakland Raiders signed him that July, seeing his potential as a contributing backup passer and a dependable kicker.

During that first season, his kicking skills helped him lead the AFL in scoring with 116 points. In two instances, his leg helped play a role in Raider victories: a trio of field goals helped upset the defending league champion Kansas City Chiefs on October 1; in the closing weeks of the regular season, Blanda booted four field goals behind a hostile Houston crowd in a 19-7 victory over his former team, the Oilers, helping gain a measure of revenge.

The Raiders went on to compete in Super Bowl II, but the following two seasons ended in heartbreak as they lost the final two AFL Championship games in the 10-year history of the league.

In 1970, Blanda was released during the preseason, but bounced back to establish his 21st professional season as one of the more dramatic comebacks in sports history. Beginning with the October 25 game at Pittsburgh, Blanda put together five straight clutch performances. Against the Steelers, Blanda threw for two touchdowns in relief of an injured Daryle Lamonica. One week later, his 48-yard field goal with three seconds remaining salvaged a 17-17 tie with the Kansas City Chiefs. Repeating the thrilling finish on November 8, Blanda once again came off the bench to throw for a pass to tie the Cleveland Browns with 1:34 remaining, then kicked a 53-yard field goal as time expired for the 23-20 win. In the team's next game, Blanda replaced Lamonica in the fourth quarter and connected with Fred Biletnikoff on a touchdown pass with 2:28 left in the game to defeat the Denver Broncos, 24-19. The incredible streak concluded one week later when Blanda's 16-yard field goal in the closing seconds defeated the San Diego Chargers, 20-17.

Blanda's eye-opening achievements resulted in his selection as the National Football League's Most Valuable Player, with Chiefs' owner Lamar Hunt commenting, "Why this George Blanda is as good as his father, who used to play for Houston." Although he never again played a major role at quarterback, Blanda would serve as the Raiders' kicker for five more seasons before being released on August 25, 1976, one month shy of his 49th birthday.

Blanda owns records as the oldest quarterback to start a title game, the oldest to play professional football, and, at 26 years, the longest career. Remaining a strong supporter of the AFL heritage, Blanda said: "That first year, the Houston Oilers or Los Angeles Chargers (24-16 losers to the Oilers in the title game) could have beaten the NFL champion (Philadelphia) in a Super Bowl." Blanda said further: "I think the AFL was capable of beating the NFL in a Super Bowl game as far back as 1960 or '61. I just regret we didn't get the chance to prove it."

He is the placekicker on the All-Time All-AFL Team, and was one of only 20 players to play all ten years of the AFL, as well as one of only three who were in every AFL game their teams played. Blanda was elected to the Pro Football Hall of Fame in 1981, his first year of eligibility, and also was inducted into the University of Kentucky Hall of Fame.

Blanda held the record for most professional football games played with 340 until September 26, 2004, when it was broken by another placekicker, Morten Andersen. Blanda is presently third in career points scored, ranking behind the aforementioned Andersen and fellow placekicker Gary Anderson. It should be noted that this category doesn't count the many passing touchdowns that Blanda scored, only his kicks and his marginal amount of rushing touchdowns.