At 6'11" (2.11 m), Salley played both power forward and center for the Detroit Pistons, Miami Heat, Toronto Raptors, Chicago Bulls, and Los Angeles Lakers. He gained the nickname "Spider" for his in-your-face style of guarding his opponent. Salley is also the first player in NBA history to play on three different championship-winning franchises; Robert Horry joined him in this exclusive club in 2005.

He was drafted in the first round of the 1986 NBA Draft out of Georgia Tech. He is among the Pistons' all-time leaders in blocked shots. He holds GT's blocked shot record and has had his jersey number 22 retired - a very rare honor in college basketball1. After joining the Pistons, he became close friends with Adrian Dantley, who taught him proper nutrition, how to exercise, and how to conduct himself off the court. Salley, for his part, called Dantley "The Teacher." Salley would become good friends with comedian Eddie Murphy and made several appearances at comedy clubs in the off-season. In 1989 and 1990, he played on two Pistons championship teams.

He was traded to the Miami Heat in 1992 and a few years after that was left unprotected by Miami in the 1995 expansion draft, following a short stint with the inaugural Toronto Raptors team where after a short stint not getting any playing time in Toronto, he negotiated a buyout of his contract in order to sign with the Chicago Bulls, where he helped Michael Jordan, Scottie Pippen and former Pistons teammates Dennis Rodman and James Edwards, lead the Bulls to a record-breaking 72-win season, after which Salley retired. However, in 1996, he came out of retirement to join Greek side Panathinaikos only for a few games. In 2000, he joined the Lakers, led by Kobe Bryant and Shaquille O'Neal. He provided a veteran post presence and locker room leadership to the Lakers en route to their first of three consecutive NBA championships from 2000-2002; he retired again following the first championship season. Currently, he is one of the hosts of The Best Damn Sports Show Period on Fox Sports Network. Salley hostedThe John Salley Block Party, a radio morning show on Los Angeles station 100.3 The Beat from May 2005-2006.

For a short time, Salley provided analysis for NBC's NBA Showtime.

Note 1 The retiring of players' jerseys is not uncommon in college basketball, but retirement of numbers is incomparably rare. The main reason is that far fewer numbers are available for use by college teams than in the NBA. NCAA rules, unlike those of the NBA, prohibit the use of any digits greater than 5 in player numbers. Georgia Tech not only retired Salley's number 22, but also the number 25 worn by Salley's teammate Mark Price.