Chris Hughton will hope his charges can stifle the Red Devils in their attempts to secure second place while adding to their own efforts to secure their top-flight status for the coming season.
José Mourinho will expect another tough test against a Brighton side that he has already beaten twice this season, in the league and in the FA Cup.
Given their solid home record, it is likely that United will find it difficult to break down a stern Brighton defense led by the likes of Shane Duffy and Lewis Dunk.
Seagulls will look to continue a solid run of results
In the past few weeks, Hughton's men have secured draws against Burnley and Tottenham Hotspur. Both teams have loftier ambitions with European football on the horizon, however, Brighton have concerns of survival of their own.
The Seagulls will hope to gain another point or even more against United. Hughton's men were unlucky to lose at Old Trafford in the reverse fixture when an Ashley Young shot was deflected into the back of the net by Dunk.
Mathew Ryan has been producing some excellent saves of late to keep Brighton alive in difficult fixtures and will hope to do the same against the visiting Red Devils.
United will look for all three points to further solidify second place status
Paul Pogba has really stepped up in recent weeks for Mourinho's side and will hope to dominate Brighton's midfield at the AMEX, alongside the resolute duo of Nemanja Matić and Ander Herrera.
Brighton boosted by the return of Davy Pröpper
Dutchman Davy Pröpper will be available for selection once again following his three-match ban. Beram Kayal has done well in his absence and Hughton might have a decision to make about which of the two to start against United.
Steve Sidwell continues to remain on the sidelines with his long-term injury, Hughton effectively has a fully-fit squad to choose from for this big game.
Romelu Lukaku a major doubt for Mourinho's side
Belgian international Romelu Lukaku has been a prolific scorer for the Red Devils this season. He suffered an injury while playing against the Gunners at Old Trafford and had to be taken off.
Mourinho will be hoping that he recovers before the major FA Cup final against Chelsea. However, Lukaku's injury presents a chance for Marcus Rashford or Anthony Martial to stake their claim for a place in the starting XI of the final.
The United boss also has the option of playing Alexis Sánchez through the middle as a frontman, the Chilean has played that role on several occasions for his country as well as former club, Arsenal.
Second-choice keeper Sergio Romero remains out injured, as Joel Pereira continues to take his place on the bench. Mourinho could also use this fixture to bring Eric Bailly back into the first- team fold.
The Ivorian has missed a lot of game time this season with his injuries and will look to regain match fitness before the all-important FA Cup final.
Three points in this fixture would seal Brighton's Premier League status, however, other results could play in their favor as well. Swansea City are set to host Southampton in a clash that could secure either club's survival.