The match at Emirates Stadium represents a chance for the Gunners to bounce back from consecutive defeats, boost their chances of getting back into the Champions League qualifying spots and dent their opponents' chances of retaining the title.
There's also the matter of payback for August's 8-2 humiliation by United at Old Trafford.
"It is a massive opportunity because you feel we have given six points away in the last two games in a way that is unbelievable," Arsenal manager Arsene Wenger said. "It is time for us to wake up and be focused. We have a good opportunity to do that against Manchester United."
But victory is just as important to United, which could draw level with Manchester City at the top of the standings with victory over Arsenal. That's if third-place Tottenham can grab a surprise win at City in Sunday's other game.
"We will go there in a positive frame of mind and try to win," Tottenham midfielder Luka Modric said. "We do that against every opponent."
United could already be ahead of City but lost back-to-back games to Blackburn and Newcastle before bouncing back with a 3-2 FA Cup win at City. A 3-0 win over Bolton then got the Red Devils back on track in the Premier League, moving them 12 points clear of fifth-place Arsenal.
United defender Chris Smalling, who has returned to action after tonsillitis, blamed a rocky patch that included Champions League elimination on injuries.
"We've probably had more injuries than any other club in the league," Smalling said. "I definitely don't think many teams have lost players of the calibre of Nemanja Vidic and Darren Fletcher for such lengthy periods. And yet we're still going strong, we're still challenging for the lead and we're even getting a few players back now, which will be crucial for the title run-in."
Arsenal can at least draw upon good home form, with only Liverpool in August winning at Emirates Stadium.
"I am confident we will get into the top four," Arsenal goalkeeper Wojciech Szczesny said. "We don't deserve to be outside the top four. We should be challenging for trophies every year and I believe the results will pick up and we will at least finish in the top four because we have the quality in the squad to succeed."
It's away from home where Arsenal is struggling, with a 2-1 defeat at Fulham and last week's 3-2 defeat at Swansea leaving the Gunners with the Premier League's worst away defence.
"I have no idea why we can't win away from home," Szczesny said. "The results speak for themselves and we have been really poor away this season. I really can't explain it. We go everywhere and try to do our best but the results don't go our way. We have talked about it and cannot come up with an answer."
City is also going through a slight dip in form with three defeats in four matches in all competitions before Monday's 1-0 win at struggling Wigan.
"It was a really important three points because it was a difficult game," City manager Roberto Mancini said. "Tottenham are having a fantastic season. They are a very good team, and it will be a fantastic game on Sunday."
Tottenham is just five points behind City, which has been its rival for a Champions League spot for the past two years. Spurs clinched a place in 2010 with a 1-0 win at City before the positions were reversed with a 1-0 win for City last season.
Spurs' players must hope last weekend's 1-1 draw with Wolverhampton Wanderers represents only a check to fans' expectations rather than the start of a decline after just one loss in 19 games.
"It's only one game: one draw doesn't suddenly mean we're not going to do this or not going to do that," Tottenham manager Harry Redknapp said. "We've been on a great run and we still are.
"We're still right up there, Champions League qualification is a real possibility for us and that's what we've got to aim to do."
Fourth-place Chelsea is at Norwich in one of eight matches Saturday, when Liverpool is at Bolton and Everton hosts Blackpool. Newcastle is at Fulham, Stoke hosts West Bromwich Albion, Sunderland hosts Swansea, Aston Villa is at Wolverhampton Wanderers, and Wigan is at Queens Park Rangers.
West Ham has the chance to take over at the top of the second tier when it hosts Nottingham Forest on Saturday, while current League Championship leader Southampton hosts Leicester on Monday.