He was arguably the most heavily recruited (for both college and the NBA) basketball prospect of his generation. Playing for the University of Virginia, he was one of only two male players in the history of college basketball to receive the Naismith Award as the National Player of the Year three times (Bill Walton of UCLA was the other male, Cheryl Miller of USC won three times, as well). He was the only player to win the Wooden award twice. Professionally, Sampson was a #1 draft pick, three-time NBA All-Star, and Rookie of the Year for the Houston Rockets. He was on the cover of Sports Illustrated an unprecedented six times in a span of less than four years (issues of December 17, 1979; December 1, 1980; March 30, 1981; November 29, 1982; December 20, 1982; and October 31, 1983).

Standing 7'4" (2.24 m) but at a lean 220 pounds (100 kg), he could dunk the ball almost without jumping yet was agile enough to dribble behind his back and often even tried to emulate the role of a point guard. For the Houston Rockets, although he was well over 7 feet tall, he played power forward and often guarded men much smaller. This was because 7'0" (2.13 m) Hakeem Olajuwon played center and the versatile Sampson preferred to play forward. Together, they were called the "Twin Towers" between 1984 and 1988.

In the 1985-86 NBA season, Sampson had (in his third season with the Rockets) lifted the Rockets from 14-68 in the 1982-83 season before his arrival to one of the best in the NBA. In Game 5 of the 1986 NBA Western Conference Finals, his last second tip-in at the buzzer beat the Los Angeles Lakers and send the Rockets to only their 2nd NBA Finals appearance in franchise history.

His NBA career quickly deteriorated as he became burdened with numerous knee injuries. In 1988, by the time he was traded to the Golden State Warriors, the rest of his career was very limited. In 1989, he was traded to the Sacramento Kings where he would basically be a third-string player. He would average 4.2 points per game and 3.0 points per game for the 1989-90 and 1990-91 seasons respectively. He would play one final year season with the Washington Bullets in 1991-92 where he averaged two points per game.

Ralph Sampson won numerous individual awards in the short period of time he was healthy, but he never won a national or NBA championship. He played in the Final Four with Virginia in 1981 and his Houston Rockets played in the NBA Finals in 1986, but each time he was turned away without winning the elusive championship. The Virginia Cavaliers returned to the Final Four in 1984 � the year after he graduated.