The Serbia international midfielder has been one of the mainstays of the United midfield this season under both Ole Gunnar Solskjaer and his predecessor Jose Mourinho.
But United will face Liverpool with Scott McTominay in the centre of the park in Matic’s place after the former Chelsea man pulled up with an injury in training on Saturday.
While the exact nature of the injury was not immediately disclosed, Matic is expected to be out for two to three weeks due to the problem.
"We tried to get him fit for the game but it wasn't to be," manager Solskjaer said of Matic's injury when speaking to MUTV ahead of kick-off on Sunday. "But we'll manage without him"
That means he will miss the Premier League meetings with Crystal Palace and Southampton in the next seven days, and will also be absent for the trip to Paris Saint-Germain for the second leg of the Champions League tie which United trail 2-0 after the Old Trafford meeting.
Matic could also be out when United travel to Arsenal on March 10, and may be a doubt also for the FA Cup quarter-final visit to Wolves six days later.
Alongside David de Gea, Matic has made the most starts of any United player this season with 32, meaning his absence will be keenly felt in the weeks ahead.
He has made a total of 81 appearances for United since signing in the summer of 2017 in a £35 million switch from Stamford Bridge.
United go into Sunday’s game off the back of their 11th win in 13 matches under Solskjaer, a 2-0 FA Cup win at Chelsea on Monday.
Besides the replacement of Matic with McTominay, United make only one other change as De Gea returns in goal in place of cup specialist Sergio Romero.