Reed was born on June 25, 1942 in Dubach, Louisiana within Lincoln Parish. He grew up on a farm in nearby Bernice, Louisiana. His parents worked to ensure Reed got an education in the segregated South. Reed showed athletic ability at an early age and played basketball at West Side High School in Lillie, Louisiana.

The New York Knicks selected Reed in the second round, with the eighth overall selection, in the 1964 NBA draft. Reed quickly made a name as a fierce, dominating and physical force on both ends of the floor. In March 1965, he scored 46 points against the Los Angeles Lakers, the second-highest single game total ever by the Knicks’ rookie. For the 1964–65 season, he ranked seventh in the NBA in scoring (19.5 points per game) and fifth in rebounding (14.7 rebounds per game). He also began his string of All-Star appearances and won the NBA Rookie of the Year Award while also being named to the NBA All-Rookie First Team.

The team continued to struggle for a few years while adding good players through trades and the draft. Dick McGuire was replaced as coach with Red Holzman, midway through the 1967–68 season. The Knicks had gone 15–22 under McGuire; Holzman steered them to a 28–17 finish. In 1968, New York’s record was 43–39, its first winning record since the 1958–59 season.

In the 1969–70 season, the Knicks won a franchise record 60 games and set a then single season NBA record with an 18-game win streak. In 1970, Reed became the first player in NBA history to be named the NBA All-Star Game MVP, the NBA regular season MVP, and the NBA Finals MVP in the same season. That same year, he was named to the All-NBA First Team and NBA All-Defensive First Team, as well as being named as ABC’s Wide World of Sports Athlete of the Year, and the Sporting News NBA MVP.

Reed’s most famous performance took place on May 8, 1970, during game seven of the 1970 NBA Finals against the Los Angeles Lakers in Madison Square Garden. Due to a severe thigh injury, a torn muscle that had previously kept him out of game six, he was considered unlikely to play in game seven. However, Reed surprised the fans by walking onto the court during warmups, prompting widespread applause. Starting the game, he scored the Knicks’ first two field goals on his first two shot attempts, his only points of the game. Following the game in the winner’s locker room, a moved Howard Cosell told Reed on national television, “You exemplify the very best that the human spirit can offer.”

Reed debuted as head coach of the New Jersey Nets on March 1, 1988, one week after the Nets’ star forward (and Reed’s cousin) Orlando Woolridge was suspended by the league and was to undergo drug rehabilitation. He compiled a 33–77 record with the Nets. In 1989, he was hired as the Nets’ general manager and vice president of basketball operations (1989–1996). During this time, he drafted Derrick Coleman and Kenny Anderson, acquired Dražen Petrović, and made the Nets a playoff contender throughout the early 1990s. Reed hired Chuck Daly to coach the Nets for the 1992–93 and 1993–94 seasons. In 1996, Reed moved to the position of senior vice president of basketball operations, with the continued goal of building the Nets into a championship contender. The Nets made the NBA Finals in 2002 and 2003.

Reed next took the position of vice president of basketball operations with the New Orleans Hornets in 2004. He retired from that position in 2007.

Rap songs have mentioned Reed, recognizing his impressive athleticism and skill. Examples include Kurtis Blow’s 1984 hit “Basketball” on his Ego Trip album, and the Beastie Boys’ “Long Burn The Fire” on their 2011 album Hot Sauce Committee Part Two.

Reed’s name has become synonymous with playing through injury, as Cris Collinsworth described an injured Aaron Rodgers as having a “Willis Reed kind of night” on the NBC Sunday Night Football broadcast on September 9, 2018.