The Red Devils were forced to withdraw Romelu Lukaku with a head injury in their draw with Southampton just 48 hours ago, while Zlatan Ibrahimović’s rushed recovery from a lengthy knee injury rules him out for a month.
Martial is therefore handed his first start as lone front-man for the Red Devils in the Premier League this season as José Mourinho makes three changes to his team. Marcos Rojo and Ander Herrera also both come in.
United, looking to end a run of three successive draws, are missing Ashley Young as he serves the first match of a three-game ban for an FA charge of violent conduct following an incident against the Saints, while fellow first-choice full-back Antonio Valencia is injured.
Luke Shaw therefore starts a third successive league game under Mourinho for the first time since September 2016.
But the Portuguese boss is also unable to call upon another former Everton man in Marouane Fellaini while Michael Carrick, Eric Bailly and Matteo Darmian all remain sidelined.
Chris Smalling and Matteo Darmian make the bench after a muscle injury and a knock respectively.
Everton boss Sam Allardyce brings former United captain Rooney back into his starting line-up after benching him for the defeat at Bournemouth two days ago, Everton's first league loss since his appointment.
Rooney takes the Everton armband in the absence of Phil Jagielka, who drops the bench.
Elsewhere, as part of seven changes from the side that lost to the Cherries, Ashley Williams, Tom Davies, Mason Holgate, Oumar Niasse and summer signing Nikola Vlašić - making just his fourth league start - all come in.
Those changes sees Aaron Lennon, James McCarthy, Gylfi Sigurdsson, Jonjoe Kenny, Dominic Calvert-Lewin and Jagielka drop out. Idrissa Gueye is missing from the team entirely.
Ex-United duo Michael Keane and Morgan Schneiderlin both start for the home side, who are without Leighton Baines, Ross Barkley, Seamus Coleman, Ramiro Funes Mori and Maarten Stekelenburg due to injury.
With Lukaku denied a return to his former club, all eyes will be on Rooney - who ended a 13-year spell with United to rejoin boyhood club Everton last summer.
He has scored 11 goals in all competitions this season, with four goals and two assists in his last three home league appearances. The 32-year-old will hope to have a huge say on the outcome.
Rooney has scored against 36 different clubs in the Premier League, less than any only three players, with United the team he has faced most - five games - without scoring against.
But Goodison has become a difficult place to visit for United in recent years, the Toffees losing just one of their last five Premier League home games against them and winning three.
Mourinho will hope that his excellent record against Allardyce - facing him 11 times without defeat and winning all five away matches - continues as United look for a much-needed uplifting three points.
Big Sam has also won just one of 21 matches as a manager against United, though that was his last home game at Sunderland back in February 2016.
Full confirmed line-ups
Everton starting XI: Pickford; Holgate, Keane, Williams, Martina; Davies, Schneiderlin; Vlašić, Rooney, Bolasie; Niasse.
Manchester United starting XI: De Gea; Lindelöf, Jones, Rojo, Shaw; Matić, Herrera; Mata, Pogba, Lingard; Martial.
Everton bench: Robles, Jagielka, Kenny, McCarthy, Lennon, Sigurdsson, Calvert-Lewin.
Manchester United bench: Romero, Blind, Darmian, Smalling, Tuanzebe, Mkhitaryan, Rashford.