It will be the 12-time winners' first ever visit to Prenton Park but their second trip to Merseyside in the space of a week, having been beaten by Liverpool at Anfield last weekend.
A third successive loss would pile more pressure on beleaguered boss Ole Gunnar Solskjaer, and Tranmere go into the game having claimed the scalp of Premier League opposition in the form of Watford on Thursday.
Here, Sports Mole looks at how the Red Devils could line up for the contest.
Eric Bailly could be set for his first start of the season having begun to build up fitness again following a lengthy absence with a knee injury.
Solskjaer was questioned in his pre-match press conference as to whether the state of the Prenton Park pitch would dissuade him from giving the Ivorian a run-out, but he suggested that Bailly may be better suited than most to cope with it, seemingly paving the way for the defender to make his first competitive appearance since April.
Solskjaer is likely to take the opportunity to give chances to youngsters like James Garner, Angel Gomes and Tahith Chong, the latter two of whom faced Tranmere for United's Under-23 side just last month.
Chong scored twice in that match, but the continuing uncertainty surrounding his future could have an impact on whether he starts this one or not.
Mason Greenwood is expected to lead the line as United look to score for the first time since it was confirmed that Marcus Rashford faces a spell on the sidelines, joining the likes of Paul Pogba and Scott McTominay on the treatment table.