Jones went down without contact in the second quarter at Allegiant Stadium while trying to evade Raiders edge rusher Maxx Crosby.
The 26-year-old fell to the floor after his knee appeared to give way, before he was taken out of the game following the first play of the quarter.
Despite not requiring a cart or assistance as he left the field, it is believed Jones suffered a torn ACL in Vegas.
According to NFL reporter Ian Rapoport, the Giants are fearing the worst after initial tests suggested he has picked up a serious knee injury, which would almost certainly end his season early.
Giants QB Daniel Jones is feared to have torn his ACL during their defeat against the Raiders
Jones, who had only just returned after missing three games with a neck injury, was four of nine for 25 yards at the time of his departure in the game.
Tommy DeVito entered the game with the Giants trailing 7-0, but by the time Jones had been ruled out for the remainder of the game at the start of the third quarter that deficit had increased to 24-0.
Josh Jacobs rushed for 98 yards and two touchdowns on 26 carries as the Raiders produced an impressive display in their first game under interim coach Antonio Pierce.
After firing Josh McDaniels on Tuesday following a string of woeful offensive performances, Las Vegas (4-5) set a new season high for points scored before the first half ended, with their previous high for a game 21.
Rookie Aidan O’Connell completed 16 of 25 passes for 209 yards in his second career start. Upon Pierce’s promotion, O’Connell was named the starting quarterback over veteran Jimmy Garoppolo.
The Giants have lost six of their past seven games and are averaging 10 points during the stretch.
Pierce was a former player with the Giants and won a Super Bowl ring when New York famously upset the previously undefeated New England Patriots in the Super Bowl following the 2007 season.