The 19-year-old forward who was the top pick in last year's NBA Draft departed during the second quarter of the Mavericks' final game, having played less than 10 minutes and scored 10 points.
"Cooper Flagg (left ankle sprain) will not return to tonight's game against the Chicago Bulls," said the Mavericks' social media account.
It was a bitter end to a regular season that was disappointing for the Mavericks, who failed to reach the playoffs, but full of personal records for Flagg.
Drafted first overall after a single college season at Duke University, Flagg this month became the first teenager to score 50 in an NBA game, during a loss to Orlando.
He also joined Michael Jordan as the only rookies to post multiple games of 45 or more points in their debut seasons.
Flagg is the favorite to win NBA Rookie of the Year, having scored 1,463 points with 462 rebounds and 315 assists.
His top competition comes from Charlotte Hornets star rookie Kon Knueppel - a college roommate and teammate of Flagg.