Paul will undergo an MRI on Friday morning. D'Antoni did not specify how long Paul would be out, saying only, "It'll be some time."
Paul played 12 minutes and had four points before exiting with 6:43 left in the second quarter and the Rockets leading 45-37.
The injury came on a relatively innocuous-looking play. Paul dribbled behind his back near midcourt while cutting right, and the ball got knocked away by Miami's Derrick Jones Jr. That was the moment when Paul grabbed the back of his left leg, the telltale sign of a hamstring issue.
He went directly to the Houston locker room, never returned and was dressed and gone before the room opened after the game.
"It's definitely tough, because he's a big-time playmaker and ball handler for us," Rockets guard Eric Gordon said. "In this offense you need all of the playmaking that you can have, and usually me, Chris, and James [Harden] have the ball in our hands trying to play-make for other people and provide good scoring."
Paul is 33 and not even half a season into a four-year, $159.7 million contract that he signed with Houston in July. He was struggling with his shot of late, connecting on 34 percent of his tries in his most recent five games entering the matchup in Miami, but he was still a big factor in Houston being able to match a season high with five straight wins.
"It's definitely going to be tough," Gordon said of the prospects of being without Paul for a while again. "But we've just got to make adjustments and play even better."
Paul suffered a right hamstring strain in the playoffs last season, missing Games 6 and 7 of the Western Conference finals -- both losses -- against the Golden State Warriors.
This season, Houston is 0-5 and has been outscored by 9.4 points per game without Paul in the lineup.
Paul has missed time because of hamstring injuries on five occasions throughout his career and a total of 19 games (including the playoffs), with his teams going 9-10, according to ESPN Stats & Information.
Paul is averaging 15.6 points, 8.0 assists and 2.1 steals this season for the Rockets, who host San Antonio on Saturday.
The Associated Press contributed to this report.