Ultimately Howell chose to play for Coach Babe McCarthy and the Mississippi State Bulldogs men's basketball program of the Southeastern Conference (SEC).

Playing for Coach McCarthy, Howell made an immediate impact as a sophomore, averaging 25.9 points and 19.7 rebounds, as Mississippi State finished 17–8, placing 3rd in the SEC.

[12][13] In his first season, Howell became friends with Piston teammate Earl Lloyd, who earlier in his career had become the first African-American to play in an NBA game.

"[3] In his second season, Howell improved to 23.6 points and 14.4 rebounds in 1960–61 as Detroit finished 34–45 under head coach Dick McGuire.

The Pistons were then defeated by the Lakers for the third consecutive year in the Western Conference Final 4–2, as Howell averaged 18.7 points in the series.

The Pistons finished 34–46, losing to Bob Pettit and the St. Louis Hawks 3–1 in the playoffs, with Howell averaging 17.8 and 10.5 in the series.

[20] With Baltimore in 1964–65, Howell led the league in personal fouls (345) and averaged 19.2 and 10.5 rebounds, playing alongside Walt Bellamy.

[20][21] The Bullets won their first round series 3–1 over the St. Louis Hawks, before losing 4–2 to the Los Angeles Lakers in the Western Conference Finals, despite 21.8 points and 13.4 rebounds from Howell.

[22] Under head coach Paul Seymour (Jeannette moved to become the GM), the Bullets finished 38–42, and Howell averaged 17.5 points and 9.9 rebounds.

[20] In Boston, Howell joined a roster loaded with future Hall of Famers: player-coach Bill Russell, John Havlicek, Don Nelson, K.C.

[24] The Celtics defeated the New York Knicks 3–1 in the playoffs, before losing 4–1 to Wilt Chamberlain and the eventual NBA Champion Philadelphia 76ers in the Eastern Conference Finals.

Howell averaged 19.8 points and 9.8 rebounds in the regular season as the 54–28 Celtics earned Russell his first title as head coach.

[26] In a rematch against Chamberlain and the 76ers in the 1968 Eastern Conference Finals, the Celtics prevailed 4–3 with a 100–96 game seven win, with 17 points and 10 rebounds from Howell.

[27] In the 1968 NBA Finals against the Lakers with Elgin Baylor and Jerry West, Howell averaged 21.0 points and 7.5 rebounds in the 4–2 series victory for the Celtics.

He was immediately traded by the Braves to the Philadelphia 76ers for Bob Kauffman and a future 1971 2nd round draft pick (Spencer Haywood).

[20] At age 34, Howell played one final NBA season with the 76ers in a slightly reduced role, averaging 10.7 points and 5.4 rebounds for the 47–35 76ers under head coach Jack Ramsey.

[32] Overall, Howell played 12 seasons (1959–1971) in the National Basketball Association (NBA) as a member of the Detroit Pistons (1959–1964), Baltimore Bullets (1964–1966), Boston Celtics (1966–1970), and Philadelphia 76ers (1970–1971).

A six-time All-Star with 17,770 career points (18.7) and 9383 rebounds (9.9), he was elected to the Naismith Memorial Basketball Hall of Fame in 1997.

[3] Hall of Fame announcer Dick Vitale called Howell the greatest offensive rebounder in history.

[34] After his career ended in 1971, Howell returned to Mississippi State earning his master's degree in physical education while assisting the men's basketball team.

[35] Howell is the father of Mississippi Board of Realtors CEO Beth Hansen and father-in-law of current University of Florida athletic director, Scott Stricklin, a Mississippi State graduate who was athletic director at his alma mater before taking the same position at Florida.

Anne Howell was a three-time All-Lone Star Conference team member and played tennis for Abilene Christian.