The striker has not featured since scoring in a 1-0 win over Arsenal on November 10 due to a groin injury, with David Moyes makes seven changes from the loss to Everton
Wayne Rooney misses out through suspension after picking up his fifth booking of the season in the 1-0 loss to Everton.
Van Persie - who Goal revealed had returned to first-team training on Friday - is one of seven changes from the midweek defeat, as the likes of Ryan Giggs, Danny Welbeck and Shinji Kagawa - who is struggling with illness - all make way.
Newcastle - whose 3-0 loss at Swansea ended a run of four consecutive wins - make just one change as Alan Pardew bolsters his midfield with Vurnon Anita coming in for striker Shola Ameobi.
Manchester United starting XI: De Gea; Rafael, Evans, Vidic, Evra; Nani, Jones, Cleverley, Januzaj; Hernandez, van Persie.
Subs: Lindegaard, Ferdinand, Anderson, Valencia, Young, Zaha, Welbeck.
Newcastle starting XI: Krul; Debuchy, Williamson, Coloccini, Santon; Cabaye, Tiote, Anita; Sissoko, Remy, Gouffran.
Subs: Elliot, Yanga-Mbiwa, Obertan, Gutierrez, Ben Arfa, Shola Ameobi, Cisse.