Reigning champions Liverpool will kick off the first of the Big Six clashes by taking on Frank Lampard's Chelsea at Stamford Bridge on September 19.
Jurgen Klopp's side - who finished 18 points clear last season - have been handed a tough start to the season with their second game being Arsenal, followed by the first Merseyside Derby in mid-October.
Runners up, Manchester City, will be eager to prove their worth after missing out on last year's title and will host Arsenal on October 17 in their first Big Six game before taking on competitors Liverpool in November.
The highly-anticipated Manchester derby will see City travel to Old Trafford on December 12 to take on United just 13 days before Christmas.
Subsequently, Pep Guardiola's men will later return the favour and host United at the Etihad for round two on February 3, 2021.
As for Manchester United, their opening game against Burnley on September 12 could be cancelled due to their Europa League campaign – meaning their return to the Premier League may be more challenging than they had first anticipated.
Ole Gunnar Solskjaer’s side face a difficult October run and may struggle to get off the mark, despite an upturn in form towards the end of last season.
The Red Devils will take on Tottenham Hotspur, Chelsea and Arsenal in the space of 27 days.
Spurs face a similar fate with a tough November and December period - with games against four members of the established 'Big Six': Manchester City, Chelsea, Arsenal and Liverpool, in the space of just 24 days.
Arsenal and Tottenham are set to go head-to-head in the North London derby on December 5, as both Mikel Arteta and Jose Mourinho battle it out for bragging rights.
December will see the Gunners face another London rival, Chelsea - who they have a mere 19 per cent win rate over - on Boxing Day.
While Chelsea will start and finish the New Year with a Big Six clash against their Manchester counterparts. The Blues will face Manchester City on January 2, before taking on Manchester United on February 2.
