Rooney returns to the squad after illness but have to make do with a substitute role, while Martial is recalled amid a run which has seen Jose Mourinho come under public criticism for his handling of the French attacker.
The other change in the United XI from the side which beat champions Leicester City 3-0 on Sunday sees Daley Blind start in place of the injured Marcos Rojo. With Phil Jones still unavailable, Chris Smalling continues alongside Eric Bailly at the heart of defence.
A victory for United over Walter Mazzarri's side would take them, temporarily at least, out of sixth spot for the first time in over three months.
The Hornets have skipper Troy Deeney leading the line, with M'Baye Niang, Mauro Zarate and Jose Holebas in close support. There is also an Old Trafford return for former Reds midfielder Tom Cleverley.
Manchester United: De Gea; Valencia, Bailly, Smalling (c), Blind; Herrera, Pogba; Mata, Mkhitaryan, Martial; Ibrahimovic. Subs: Romero, Rooney, Lingard, Carrick, Rashford, Fellaini, Darmian.
Watford: Gomes; Cathcart, Kaboul, Prodl, Britos; Cleverley, Capoue; Niang, Zarate, Holebas; Deeney (c). Subs: Arlauskis, Mariappa, Janmaat, Behrami, Doucoure, Success, Okaka.