The Serbian international was withdrawn early in the second half in the Red Devils' 4-2 win over Watford at Vicarage Road. He was replaced by Ander Herrera in the 54th minute. United manager Jose Mourinho confirmed the midfielder has picked up an "important" injury.
"For Nemanja Matic to tell me he wants to be replaced, he does not do that if it's nothing important. It is muscular," Mourinho said in his post-match press conference.
According to the Manchester Evening News, Matic was "walking gingerly" through the mixed zone at Vicarage Road. They also claim the former Chelsea star remains doubtful to face Arsene Wenger's side.
The Portuguese tactician was already without Marouane Fellaini for their trip to Watford. Mourinho also confirmed the Belgium international picked up an injury. United are unsure of the extent of his knock.
Mourinho has the services of Paul Pogba, Herrera, Michael Carrick and Scott McTominay as the other midfielders in the squad. Carrick has made only one appearance for the 20-time English champions this season.
The former Tottenham Hotspur man revealed he was recovering from a heart procedure, which kept him out of action since September. It is unlikely the 36-year-old would be ready to feature against Arsenal.
With Matic doubtful and Fellaini struggling with a knee injury and Carrick recovering, Mourinho and United could be without three midfielders for their trip to face Arsenal. Herrera is likely to start against the north London club and partner Pogba in the heart of the midfield.
The ex-Real Madrid and Chelsea manager switched to a three-man defence in their latest league win over Marco Silva's side. Mourinho is likely to use the same formation with Jesse Lingard likely to retain his place in the starting XI, when they face Arsenal.
Lingard assisted Ashley Young's first goal before going on to score a brilliant goal in the final quarter against Watford.
Meanwhile, Arsenal will be without their club-record signing Alexandre Lacazette for the clash against United. The France international suffered a groin injury in the Gunners' 5-0 win over Southampton on 29 November.