The match was delayed for about five minutes as Lukaku received treatment, with the Belgian striker apparently administered oxygen.
When it became clear the striker would play no further part in proceedings he was carried off the pitch to applause from the stands.
With fellow striker Zlatan Ibrahimovic left out of the match-day squad, Marcus Rashford got the nod to replace the Belgium international in an early substitution.
8' - Play is paused while Lukaku receives treatment after a clash of heads. Moments earlier, @D_DeGea made a great save to deny Southampton an early goal. #MUFC #MUNSOU — Manchester United (@ManUtd) 30 de diciembre de 2017
Lukaku had missed a key opportunity moments before the collision, sending an unmarked header over the bar after being teed up by Juan Mata.
Zlatan Ibrahimovic, a natural option to replace Lukaku in Jose Mourinho's line-up, was not a part of the game-day squad.
Lukaku has scored 15 goals in all competitions since joining the Red Devils in a £75 million move from Everton this past summer.
The injury likely rules out the 24-year-old for United's New Year's Day meeting with his former club at Goodison Park.