After the game, Pompey reported that an X-ray was negative and he'll be re-evaluated Tuesday.
The rookie played 35 minutes but was forced to leave the court before the final buzzer after hurting his ankle. He had 10 points, eight rebounds and three steals in the 113-91 loss.
Simmons missed Saturday's game against the Orlando Magic with an elbow injury but returned for an anticipated battle against LeBron James and the Cavs. James showed why he is still a far superior player with 30 points, 13 rebounds and six assists in the win.
Still, the Sixers star has exceeded most expectations this year in his first action after being taken with the No. 1 overall pick in 2016.
The 21-year-old entered the day averaging 18.5 points, 9.1 rebounds, 7.7 assists and 2.1 steals per game, tallying 11 double-doubles and two triple-doubles in just 17 games.
His play alongside Joel Embiid has helped the 76ers to an 11-8 record to start the year, a significant turnaround for a franchise that hasn't had a winning season in six years.
If Simmons is forced to miss more time, T.J. McConnell will likely take over at point guard in a more traditional lineup for Philadelphia.