Manchester United visit the Emirates Stadium on New Year's Day to take on an Arsenal side that snatched defeat from the jaws of victory against Chelsea on Sunday.
Premier League leaders Liverpool will be aiming to win an 11th game in a row in the English top flight when they host Sheffield United at Anfield on Thursday.
Jose Mourinho's Tottenham Hotspur, meanwhile, travel to Southampton in Week 21, Manchester City host Everton and Chelsea visit Brighton & Hove Albion.
Week 21 Fixtures and Picks
Wednesday, January 1
12:30 p.m. GMT/7:30 a.m ET: Brighton & Hove Albion 1-2 Chelsea
12:30 p.m. GMT/7:30 a.m ET: Burnley 1-0 Aston Villa
3 p.m. GMT/10 a.m. ET: Newcastle United 0-2 Leicester City
3 p.m. GMT/10 a.m. ET: Southampton 1-3 Tottenham Hotspur
3 p.m. GMT/10 a.m. ET: Watford 2-2 Wolverhampton Wanderers
5:30 p.m. GMT/12:30 p.m. ET: Manchester City 3-2 Everton
5:30 p.m. GMT/12:30 p.m. ET: Norwich City 1-1 Crystal Palace
5:30 p.m. GMT/12:30 p.m. ET: West Ham United 2-2 Bournemouth
8 p.m. GMT/3 p.m. ET: Arsenal 1-2 Manchester United
Thursday, January 2
8 p.m. GMT/3 p.m. ET: Liverpool 3-0 Sheffield United
There were signs of improvement for new manager Mikel Arteta when Arsenal took on Chelsea on Sunday.
But familiar failings saw the Gunners come away from the fixture with nothing after Jorginho and Tammy Abraham scored in the last 10 minutes to turn the game on its head following Pierre-Emerick Aubameyang's first-half goal.
It means Arsenal are now winless in five in all competitions going into Wednesday's clash with United.
Ole Gunnar Solskjaer's side have blown hot and cold this term, but they have been largely excellent against the Premier League's bigger sides, beating City, Spurs, Chelsea and Leicester, and drawing with Liverpool.
Arsenal may sit 12th in the table, but they remain one of England's top clubs, and the rivalry between them and the Red Devils is a storied one.
The key danger Arteta will have to protect against is United's pace on the counter-attack, which City were unable to deal with when the Red Devils visited the Etihad Stadium earlier this month.
Marcus Rashford and Anthony Martial are both in fine goalscoring form, and they will be relishing the prospect of taking on Arsenal's fragile defence:
Liverpool, meanwhile, will continue their seemingly inexorable march towards a first league title in 30 years when they face the Blades.
Chris Wilder's Sheffield United have been largely brilliant in their first season back in the top flight in over a decade, and they sit eighth in the table:
Sunday's 2-0 defeat at champions City came on the back of a 1-1 home draw to Watford, though, and Jurgen Klopp's side will be confident of picking up another three points against a side they beat 1-0 in the reverse fixture back in September.