Tagovailoa, who had endured a miserable night throwing three interceptions, was hurt with 4:24 remaining in the third quarter and with his team already 31-10 down.
Running with the ball on a fourth down, Tagovailoa lowered his head into the body of Bills defensive back Damar Hamlin.
After receiving on-field treatment, the quarterback left the field under his own power. Miami later confirmed he had been taken out and replaced by Skylar Thompson due to a concussion.
Tagovailoa endured a series of injuries during the 2022 season, including two documented concussions which raised questions over his long-term future in the game. He stayed injury-free last season.
Miami coach Mike McDaniel said the 26-year-old would undergo a full evaluation on Friday and said it was too early to know how long he would be sidelined for.
"Right now it is more about getting a proper, procedural evaluation and then taking it one day at a time. The furthest thing from my mind is what is the timeline -- I am just worried about my team-mate like the rest of the guys are," said McDaniel.
The injury came after Buffalo had emphatically shown they have no intention of giving up their domination of the AFC East, looking far superior to their rivals in all areas.
The Bills, led by quarterback Josh Allen, have won the last four AFC East divisional titles and Allen now has an 11-2 regular-season record against the Dolphins.
'Supreme disappointment'
Miami's night to forget began with Tagovailoa throwing an interception on their first drive and with the ball in Allen's hands, he led them to an early touchdown ending with a 17-yard pass to James Cook.
The Dolphins responded with a 10-play, 70-yard drive which concluded with a five-yard touchdown pass from Tagovailoa to De'Von Achane.
The Miami quarterback then threw another interception when he was well off-target with a pass intended for receiver Robbie Chosen but which was easily picked off by Christian Benford.
A 43-yard field goal from Tyler Bass on the resulting possession put Buffalo 10-7 ahead but any hopes the home crowd had of a shoot-out in the heat soon dissipated as Buffalo took control.
Allen found Taron Johnson with a superb 33-yard pass and Cook finished off the drive with a one-yard run for the touchdown.
The Bills extended their lead to 24-7 with Cook rushing 49 yards for his third touchdown on the opening play of the drive and Miami's only response was a field goal which sent them 14 points down at the interval.
Tagovailoa's third interception of the night came in the third quarter and was a "pick six" with Ja'Marcus Ingram returning it 31 yards into the end-zone.
Then came Tagovailoa's injury, adding fresh concerns over his durability on a night when Buffalo showed they remain a cut above their closest divisional rivals of recent seasons.
Allen finished with 139 yards on 13/19 passing and one touchdown while Miami-born Cook ended with two rushing touchdowns from his 78 yards from 11 carries along with one touchdown receiving.
"When you come back home, you've always got to put on a show, so I just stayed locked and gave my team the W," said a grinning Cook.
McDaniel said Miami's loss left a feeling of "supreme disappointment" and said there had been some "absolutely catastrophic" mistakes in the game.
"I think it's a gut check for the team early in the season... it's one loss that really cuts deep, but that can be a good thing or a bad thing depending on how you respond to it," he added.
