He played for the 76ers, the Golden State Warriors, the Miami Heat, the Cleveland Cavaliers, the New York Knicks and the Houston Rockets, averaging 11.5 points per game throughout his career.

He is first on the school's all-time list in rebounding, blocked shots, and minutes; is second in scoring (just six points behind all-time leader Nick Revon); and third in points per game, field goals made, field goal percentage, free throws made and attempted, and steals.

The Golden Eagles fell to NC State on March 14, 1991, in the opening round of the East Regional, 114–85, and Weatherspoon scored 21 points.

It was the second straight season USM had made the NCAA tournament; in 1990 they had lost 79–63 in the opening round to La Salle.

Weatherspoon became the first Golden Eagle to have his jersey retired when his #35 was raised to the rafters on March 7, 1992, on the night of his final home game.

Spoon, listed at 6'7" but appearing closer to 6'5", was, like Barkley, an undersized power forward with a strong desire for rebounding and operating underneath the basket.

The Sixers included many lottery picks on the team: Weatherspoon, Shawn Bradley, taken second in 1993, and Sharone Wright, taken sixth in 1994.

Lucas drafted Jerry Stackhouse third overall in 1995, and in retained several unpredictable players, including Vernon Maxwell and Richard Dumas.

Within the season's opening month they had traded Bradley to New Jersey for Derrick Coleman, and the Sixers, while talented, were never able to develop consistency, save for Weatherspoon.

On the final day of the regular season, in a game at Toronto, Weatherspoon scored a career-high 35 points to go with 14 rebounds and 7 blocks.

Weatherspoon saw his role reduced, averaging 12.2 points and 8.3 rebounds for a Sixers team that battled injuries, consistency, and maturity.

The trade fell through after Radja failed his physical, and the Sixers' lack of communication with Weatherspoon, after five years of service, during this time angered him.

That trade did not occur until February when Philadelphia sent Weatherspoon and Jim Jackson to Golden State for Joe Smith and Brian Shaw.

In 2022, Weatherspoon was named an assistant coach for the men's basketball team at Jones County JC in Ellisville, Mississippi.