This is a fixture the Toffees have not won since 1992 and their record in the 19 games to follow that match reads a sobering four draws and 15 losses.
David Moyes will have his work cut out trying to secure a result, although last season's memorable 4-4 draw will surely dominate most tactical discussions in the build up.
In one of the games of the season, Everton twice came back from a two goal deficit to claim a point and substantially derail United's title challenge.
With Sir Alex Ferguson's side nine points clear in this season's Premier League race, there's more of an onus on the Toffees to find a result to prolong their push for fourth.
Here's a look at how Moyes should go this time around.
Everton Team: (4-4-1-1)
Tim Howard; Phil Neville, Phil Jagielka, Sylvain Distin, Leighton Baines; Kevin Mirallas, Darron Gibson, Leon Osman, Steven Pienaar; Marouane Fellaini; Victor Anichebe.
In front of Howard, who would obviously start in goal, there would be a slight reshuffle. Neville returns to captain the side, and John Heitinga—who was simply dire against Aston Villa—drops out of the lineup.
Neville rarely plays right-back at this advanced stage of his career, unable to bomb forward and back as he would in his prime. However, with Tony Hibbert and Seamus Coleman still on the sidelines, there are few viable alternatives.
Old Trafford is perhaps also one of the few grounds he can get away with this, as it's more important he solidifies the back four instead of linking up in attack. Neville's presence is also beneficial for the Toffees and, simply put, there's no place for him in midfield.
This would leave Jagielka slotting back to his more accustomed role of centre-back, where he's been one of the Toffees' most consistent players this season. It's been a waste keeping him at full-back.
The midfield is unchanged and picks itself. In the middle, Gibson plays the deeper role, defensively minded while spraying diagonals as Osman helps recycle the ball and joins in with attacking interplay.
Either side of them, Pienaar and Mirallas will be pivotal in attack, but will also need to stay alert and track their man.
With Neville unlikely to maraud forward an excessive amount, Mirallas will have a licence to roam into central areas and become a nuisance to mark. Pienaar will also drift in slightly, as he waits to link up with an overlapping Baines.
Given Fellaini's imposing performance in both the 4-4 draw last year and Everton's 1-0 home win at the start of this season, he must play in an advanced role just off the striker.
United have had trouble dealing with his aerial ability in the past and the Toffees must look to capitalise on this and seek out the Belgian at every opportunity. He will also provide a handy outlet when clearing the ball from defence.
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After the Neville, Heitinga selection, the next most taxing choice is over Anichebe and Nikica Jelavic in attack.
Despite a barren few months, Jelavic returned to scoring ways for Croatia this week, finding the net with a trademark one-touch finish from a Luka Modric through-ball. He also scored twice in last season's 4-4 draw with a pair of opportunistic strikes.
However, as much as the Croatian's quality is needed, Anichebe has been in the best form of his career and was once again impressive against Aston Villa. He deserves to keep his place.
The Nigerian's energy and commitment will be useful, especially with United likely to maintain to lion's share of possession. Jelavic would then be a good option to add in the last 30 minutes, with a result hopefully still in reach.