The central midfielder - who was criticised by Liverpool icon Graeme Souness for playing like a "schoolboy" this weekend - was dropped for United's win over Huddersfield Town after a poor performance in their defeat at Tottenham on January 31.
Alexis Sanchez makes his fourth consecutive start since signing for the Red Devils in the January transfer window from rivals Arsenal, although he's never scored against the Magpies in the Premier League in four attempts.
Anthony Martial, Jesse Lingard and Romelu Lukaku also feature in an expensively-assembled attack against a Newcastle side that haven't won at home in the league in the last eight games.
Luke Shaw is excluded despite a position showing against Huddersfield, with Ashley Young stepping back into the left-back slot. Phil Jones also returns for Marcos Rojo, while Marcus Rashford fails to feature in the matchday 18 for the first time this season.
In Rafa Benitez's side's favour is the fact that Mourinho has never won a Premier League match at St James' Park in six attempts, although he has triumphed twice at the ground in the League Cup.
Nemanja Matic, who starts alongside Pogba in midfield, told Sky Sports ahead of the game: "I've played here a couple of times, it's always difficult when they play good football [because] the crowd is behind them for 90 minutes.
"So, we know it's going to be hard for us, but we know what we have to do, we've prepared for the game well, so I hope we can get all three points here.
"I think that their concentration is on a higher level [because of the threat of relegation] and, for sure, they fight every game like it's their last one because they know they are in danger.
"So, it's going to be hard like every game."
Newcastle XI: Dubravka; Yedlin, Lascelles, Lejeune, Dummett; Ritchie, Shelvey, Diame, Kenedy, Perez; Gayle. Subs: Darlow, Murphy, Hayden, Manquillo, Joselu, Merino, Atsu.
Man Utd XI: De Gea; Valencia, Smalling, Jones, Young; Matic, Pogba; Sanchez, Lingard, Martial; Lukaku. Subs: Romero, Lindelof, Rojo, Mata, Carrick, Shaw, McTominay.