The Red Devils have been mysteriously quiet about the striker's injury, but reports are claiming that he will miss up to three weeks with an ankle problem.
Another fitness setback for Van Persie capped off a miserable day for United in Wales as they surrendered the lead to fall to the Swans for the second time this season.
Sections of United fans had been calling for Herrera's inclusion for some time and will hope that his goal against Swansea will earn the £28m signing from Athletic Bilbao just his eighth Premier League start of the season.
Van Gaal seems to be giving 4-4-2 a go at last and, with Wayne Rooney returning to his striking roots, Marouane Fellaini may get the nod ahead of Juan Mata at the point of the diamond in a triumph of physicality over finesse.
Radamel Falcao was an unused substitute last weekend, but should return to the starting lineup as cover for Van Persie, with alternative James Wilson having picked up a knock to join the former Arsenal forward and Michael Carrick on the sidelines.
Van Gaal may revert to the more attacking right-back option of Antonio Valencia, leaving Paddy McNair, who was hooked at half time against the Swans, to be demoted to the bench alongside Ashley Young and Adnan Januzaj.
Last weekend's stalemate against West Bromwich Albion at the Stadium of Light was Sunderland's seventh 0-0 draw of the season and left them only three points above the drop zone, and goalless in three games.
Confidence is low around Wearside, as evidenced by Gus Poyet's open letter to the fans, but a result at Old Trafford would give them a much-needed lift ahead of a huge midweek match against relegation rivals Hull City.
They did manage to hold the Red Devils to a 1-1 draw back in August, and Poyet will hope that the inside knowledge of former United centre-back pairing Wes Brown and John O'Shea can assist them to a similar outcome.
Lee Cattermole's return was one of few positives for the Black Cats to take from another toothless display against the Baggies. Sunderland won only one league match during his six-week layoff with knee and groin problems.
Worse news on the fitness front for Sunderland is that Emmanuele Giaccherini may not play again this season because of an ankle injury. Billy Jones and Will Buckley are also sidelined for their trip to the Theatre of Dreams.
Poyet's two expected changes could see a left-sided pairing of Patrick van Aanholt and Connor Wickham. Both were used from the bench against Albion, but could be recalled at the expense of Anthony Reveillere and Ricky Alvarez.
United have lost just twice in 24 encounters with Sunderland and have won seven of their last eight home games.
Form in Premier League: LWWDWL
Form in all competitions: WWDWWL
Possible starting lineup: De Gea; Valencia, Jones, Rojo, Shaw; Blind, Di Maria, Herrera; Fellaini; Rooney, Falcao
Form in Premier League: LLWDLD
Form in all competitions: WWDLLD
Possible starting lineup: Pantilimon; Vergini, O'Shea, Brown, Van Aanholt; Cattermole; Wickham, Larsson, Gomez, Johnson; Defoe
Sports Mole says: 2-0