After a brief stint in the military at the end of World War II, Graham played for the Rochester Royals of the National Basketball League (NBL), winning the 1945–46 championship.

Graham's 1946 NBL and AAFC titles made him the first of only two people to have won championships in two of the four major North American sports (the second was Gene Conley).

Born into a family of four boys in Waukegan, Illinois, Graham set a first state record at birth weighing 14 lbs 12 oz.

[5] Encouraged by his parents—his father having taught famous comedian Jack Benny—[6] he took up several instruments: the piano, violin, cornet and French horn.

[10][11] Graham did not take up football until his sophomore year, when Northwestern coach Pappy Waldorf saw him throwing in an intramural game and invited him to practice with the team.

Graham's first game for the Northwestern Wildcats football team was on October 4, 1941, when he caught a Kansas State punt and returned it 90 yards for a touchdown.

[10][14] As America's involvement in World War II intensified after the December 7, 1941, attack on Pearl Harbor, Graham signed up for service alongside many fellow student-athletes, entering the U.S. Coast Guard.

[10][15] Graham still had 89 completions, setting a single-season passing record in the Big Ten Conference, a division of major college teams from the Midwestern United States.

[18][19] The Wildcats lost to Notre Dame and Michigan, however, and finished the season with an 8–2 record and a ninth-place ranking in the AP Poll.

[18][19][20] Graham set another Big Ten passing record, was named the conference's Most Valuable Player, received All-American honors and finished third in Heisman Trophy voting.

[7][20] Graham's career at Northwestern officially ended in February 1944, when he moved to Colgate University in Hamilton, New York, in the Navy's V-5 cadet program, a pilot training course.

[20][26] Impressed by Graham's performances in Northwestern's wins over Ohio State in 1941 and 1943, Paul Brown came and offered him a contract worth $7,500 per year ($127,000 in 2023 dollars) in 1945 to play for a professional team he would be coaching in Cleveland in the new All-America Football Conference (AAFC).

"[27] Graham was also drafted by the National Football League's Detroit Lions, but he did not sign a contract or play a game with the team as the war wore on.

[32][33] Handing the ball to fullback Marion Motley and throwing to ends Dante Lavelli and Mac Speedie, Graham led the team to a 12–2 regular-season record and a spot in the championship game against the AAFC's New York Yankees.

[44] "I remember his tremendous peripheral vision and his great athletic skill, as well as his ability to throw a football far and accurately with just a flick of his arm", Brown said.

Graham was voted the United Press NFL Player of the Year[46] and led the Browns to a 10–2 record, which set up a playoff against the New York Giants for a spot in the championship game.

[49] With the game tied 3–3 in the fourth quarter, Graham gained 45 yards by running with the ball on a long drive to set up a 28-yard Lou Groza field goal that put the Browns ahead 6–3.

[57] With Graham at quarterback, Cleveland finished the 1952 season with a 9–3 record and faced the Detroit Lions in the NFL championship game.

[58] Despite gaining 384 total yards to Detroit's 258, Graham, who was the NFL Player of the Year,[46] and the Browns lost their second straight championship, 17–7.

[59] Cleveland had several long drives that ended with missed field goals, and a fourth-quarter touchdown was negated because Graham's throw to Pete Brewster was first tipped by receiver Ray Renfro; under rules in place at the time, balls deflected by offensive teammates were automatic incompletions.

[60] After the season, as Graham was practicing for the Pro Bowl in Los Angeles on January 2, 1953, his six-week-old son Stephen died from a severe cold.

[63] Near the end of the season in a game against the 49ers, Graham took a forearm to the face from Art Michalik that opened a gash on his chin requiring 15 stitches.

[77] When Brown took Graham out of the game in the fourth quarter, the crowd in the Los Angeles Coliseum gave him a standing ovation.

[90] Following his convincing win in the all-star game, Graham's friend George Steinbrenner helped get him a job as the head football coach for the Coast Guard Academy in New London, Connecticut.

[95] Graham was offered coaching jobs in the NFL numerous times during his tenure at Coast Guard, but he said in 1964 that he was content to stay at the small school on a $9,000 salary.

[96] Despite his reservations about the professional game, Graham, who moonlighted as a television and radio commentator for the American Football League's New York Jets in 1964 and 1965, left the Coast Guard Academy after seven years in 1966 to become head coach and general manager of the NFL's Washington Redskins,[97][98][99] Graham's three seasons (1966–1968) were similarly unsuccessful, with an overall record of 17–22–3.

[102][103] After being dismissed as the Redskins' coach, Graham returned to the Coast Guard Academy as athletic director and said he planned to stay there until he retired.

[108] In 1974, Graham was named Coast Guard's football coach once again, although he resigned two years later to focus on his duties as athletic director.

[112] An avid golfer and tennis player, Graham partnered with New York Yankees great Joe DiMaggio in numerous golf tournaments later in life.

[114] In 2013, Northwestern's fundraising department created the Otto Graham Society to honor his achievements at the school and support its athletics programs.