Fitzsimmons played college basketball at Hannibal-LaGrange, where his jersey is now retired. He got his first coaching job at Moberly Junior College in Moberly, Missouri in 1956. He coached there eleven years, capping his tenure with two national junior college championships (NJCAA), in 1966 and 1967. In 1968, Fitzsimmons was hired by Kansas State University, where he served as head basketball coach for only two seasons before going into the NBA.
National champion Postseason invitational champion Conference regular season champion Conference regular season and conference tournament champion Division regular season champion Division regular season and conference tournament champion Conference tournament champion
In 1970, Fitzsimmons replaced Jerry Colangelo as Suns coach. He took the team to their first winning season, going 48-34 that season.
In 1972, Fitzsimmons went on to coach the Atlanta Hawks. He would return to Phoenix in 1975, to become a permanent resident, although he still coached the Hawks. According to Fitzsimmons, one of the main reasons he accepted a job as Hawks coach was the opportunity to coach Pete Maravich. In 1976, he became the player personnel director for the 1975 NBA champion Golden State Warriors.
In 1977, Cotton Fitzsimmons was hired as head coach by the Buffalo Braves. He lasted there one season, being hired by the Kansas City Kings to be their head coach for the next season. With the Kings, he won the NBA "Coach of the Year" award in 1979.
In 1984, his profession took him to San Antonio, Texas, where he was head coach of the Spurs. One year later, in 1985, he was inducted into the National Junior College Hall of Fame.
Cotton Fitzsimmons was criticized both by Suns fans and basketball critics after the trade; Nance was very popular in Phoenix. But the Suns had come off a chaotic 1987–1988 season in which they only won 28 games and lost 54, and the team had been shaken by a drug scandal.  With the first round draft pick of 1988, the Suns chose Dan Majerle, and the franchise had a turn-around season, winning 55 games and losing 27 before advancing all the way to the Western Conference's Finals that season, where they were swept by the Los Angeles Lakers.
During the '88 Draft when Majerle was booed by the fans, Fitzsimmons publicly chastised them by saying, "you'll be sorry that you booed this young man."
After another successful season, the Suns returned to the NBA Playoffs in 1990. This time around, they returned the favor on the Lakers, beating them 4 games to 1 at the Western Conference's Semi-Finals, but once again, Fitzsimmons' team fell short at the NBA's Western Conference Finals, losing to the Portland Trail Blazers, 4 games to 2.
In 1991, the Suns lost to the Utah Jazz at the Western Conference Playoffs' first round, 3 games to 1. During the rest of the playoffs, Fitzsimmons served briefly as a color commentator for NBC, most notably, alongside Marv Albert for Game 4 of the Eastern Conference Finals between the Chicago Bulls and the Detroit Pistons. In 1992, Cotton Fitzsimmons became only the sixth coach in NBA history to reach 800 wins. After losing to the Trail Blazers at that year's Western Conference Semi-Finals, 4 games to 1, Fitzsimmons retired as coach, to work as Suns senior executive vice-president. By then a long-time friend of Colangelo, he helped Colangelo decide to trade Jeff Hornacek, Andrew Lang and Tim Perry for Charles Barkley, while also helping with the decision of signing free agent Danny Ainge. He also did television commentary, joining Al McCoy for Suns broadcasts.
In 1996, he returned to the Suns as head coach for the third time, helping the Suns reach the NBA Playoffs, where they lost to the Spurs, 3 games to 1.
The 1996-1997 Suns lost their first eight games, and Fitzsimmons resigned as head coach of the Suns. At the moment of his retirement, he had 832 wins and 775 losses, making him the eighth winningest coach in NBA history. He has since slipped to number ten in the all-time winning list as an NBA coach.
Fitzsimmons was diagnosed with lung cancer later on in life. His family chose to keep his health status private. Months after being diagnosed with cancer, his condition worsened because of a brain stroke. He suffered two more brain strokes before it was finally revealed to the public that he was in serious condition at a local hospital. On July 25, 2004, the morning after his death, the Arizona Republic's sports section's headline read: "Brightest Sun Fitzsimmons dies."
Fitzsimmons was very popular among Phoenix Suns fans and in the organization, and was inducted into the team's Ring of Honor in 2005. He is also a member of the Missouri Sports Hall of Fame and the National Junior College Hall of Fame.
A horse race at Turf Paradise in the Phoenix area is named for Fitzsimmons, the Cotton Fitzsimmons Mile Handicap. Horses must be four years of age or older, and weight is based on past performances.