Rashford replaces Romelu Lukaku as the attacking spearhead following the Belgian's foot injury sustained against the Gunners, while Martial comes in for Alexis Sanchez with the Chilean rested and spared the travel to the south coast.
Ander Herrera steps aside for the promotion of Fellaini, while Matteo Darmian, Juan Mata and Marcos Rojo replace Victor Lindelof, Antonio Valencia and Jesse Lingard as Mourinho shuffles the pack ahead of the FA Cup final in two weeks' time.
United need four points to be assured of second place at the end of the season, while a win at the Amex Stadium would be enough to secure third at the very least.
Chris Hughton's Brighton will be a Premier League team again next term should they beat United in the Red Devils' first-ever visit to the Amex.
Brighton XI: Ryan; Bruno (c), Dunk, Duffy, Bong; Knockaert, Stephens, Propper, Izquierdo; Gross; Murray.
Subs: Krul, Goldson, Schelotto, Kayal, March, Locadia, Ulloa.
Man Utd XI: De Gea; Darmian, Smalling, Rojo, Young (c); Fellaini, Matic, Pogba; Mata, Rashford, Martial.
Subs: Romero, Lindelof, Bailly, Lingard, Shaw, McTominay, Herrera.