Creekmur played professional football in the National Football League (NFL), principally as an offensive tackle and offensive guard, for the Detroit Lions for ten years from 1950 to 1959. He appeared in every pre-season, regular season, and post-season game played by the Lions from 1950 to 1958—a streak of 165 consecutive games. He played in eight consecutive Pro Bowl games from 1950 to 1957 and was selected by the Associated Press as a first-team All-Pro player seven consecutive years from 1951 to 1957. During Creekmur's tenure with the team, the Lions advanced to the NFL championship game four times and won the championship in 1952, 1953, and 1957.
Creekmur was drafted by the Philadelphia Eagles in the 26th round, 243rd overall pick, of the 1948 NFL Draft, but continued playing college football in 1948 and 1949. He was acquired by the Detroit Lions prior to the 1950 NFL season and spent his entire NFL career with the Lions. Beginning with the 1950 season, Creekmur appeared in every pre-season, regular season, and post-season game played by the Lions from 1950 to 1958—a streak of 165 games. He played through multiple injuries, including dislocated shoulders, knee injuries, and one whole season with a crushed sternum.
Creekmur began his career with the Lions as an offensive guard for two years and then moved to the offensive tackle position, though he also played some on defense as well. He was considered an "outstanding blocker" for Detroit teams that featured backfield stars Bobby Layne and Doak Walker. He played in eight consecutive Pro Bowl games from 1950 to 1957 and was selected by the Associated Press as a first-team All-Pro player six times in seven years from 1951 to 1954 and 1956-1957. With Creekmur in the line, the Lions advanced to the NFL championship game four times and won the championship in 1952, 1953, and 1957.
During his rookie season, Creekmur was the victim of a highly publicized extortion attempt in which a "notorious hoodlum" schemed with others to falsely accuse him of sexual assault on a night club dancer. Two individuals were later convicted after a trial in the matter.
Near the end of the 1958 season, Creekmur, at age 31, announced that he would retire at the end of the season, ending his 168-game playing streak. The Lions held a "Lou Creekmur Day" for their December 14, 1958, game against the New York Giants. In October 1959, after the Lions lost their first four games, the Lions persuaded Creekmur to return to the club. Creekmur appeared in the final eight games of the 1959 season.
During his playing career, Creekmur worked a second job as the terminal manager for the Saginaw Transfer Company and made more money as terminal manager than he did as an All-Pro football player.
After retiring from football, Creekmur worked for a time in the 1960s and 1970s for Ryder Trucks as a director of labor relations and later as vice president of labor relations in Florida.
Creek received numerous honors, including the following:
In 1975, sports writer Joe Falls named him one of his 11 greatest Lions.
In 1976, sports writer George Puscas jokingly dubbed Creekmur as "perhaps the finest holder of all time". Puscas recalled that Creekmur would cup his hands in front of his chest to "grab a handful of jersey, or the edge of a shoulder pad" and noted: "I remember telling Creekmur in his late years that I would spend the entire game just watching him, to make note and study of his craftmanship and perhaps compose an essay on it."
In 1983, Puscas included Creekmur on his all-time Lions team.
In 1996, he was inducted into the Pro Football Hall of Fame in his 32nd year of eligibility—at that time, a record wait for an inductee. Creekmur said at the time, "I kept falling through the cracks."