City, who hold a one-point advantage at the top of the table with five games remaining, travel to Leeds, who are also in need of the points to guarantee survival.
Liverpool can go top for a few hours at least if they win at Newcastle, but the Magpies have won their last six home games to storm into the top half of the table since beginning to splash the cash of the Saudi sovereign wealth fund in January.
The Premier League’s top two remain on course to end their season with another showdown in the Champions League final after seeing off Spanish opposition in contrasting fashion in midweek.
City should have put Real Madrid out of sight in a thrilling 4-3 win over the 13-time European champions, while Goliath got the better of David as Liverpool beat Villarreal 2-0.
Champions League considerations could play a major role in the team selection of both title contenders.
Jurgen Klopp gave Liverpool fans even more cause for celebration by extending his contract at Anfield for a further two years to 2026 on Thursday.
However, the German is far from happy at the scheduling of a lunchtime kick-off just three days after a Champions League semi-final.
“It’s brutal but it’s fine. It’s the best situation you can have,” said Klopp.
“Just go for the next one and try to play the best football you can.”
City boss Pep Guardiola has a tough balancing act in selecting his side for what is expected to be an energy-sapping visit to Elland Road before their blockbuster return leg at the Santiago Bernabeu.
– ‘Best in the world’ –
Leeds are unbeaten in five games, but are just five points clear of the relegation zone ahead of a tough run-in, with Arsenal and Chelsea to come after the visit of City.
“I think it is the ultimate test,” said Leeds manager Jesse Marsch. “I’m very honest when I say that I think they are the best team in the world.”
Everton have a game in hand to cut the gap on Leeds down to two points, but the Toffees’ 68-year stay in the top flight is at serious risk.
Frank Lampard could do with a favour from his old club as Chelsea visit Goodison Park on Sunday.
By the time they kick off, Lampard’s men could find themselves five points adrift of safety should Burnley continue their upturn in form since sacking Sean Dyche.
The Clarets have taken seven points from a possible nine under caretaker boss Mike Jackson and will be confident of another huge win when they travel to Watford.
The Hornets have lost 10 consecutive home games and their return to the Championship would be virtually confirmed by another defeat.
A Burnley victory would also mathematically relegate Norwich, should they lose at Aston Villa.
The battle to join City, Liverpool and Chelsea in next season’s Champions League looks like a shootout between north London rivals Arsenal and Tottenham.
Arsenal have a two-point advantage and both sides will be confident of victory this weekend against opposition with European semi-finals on their mind.
The Gunners travel to West Ham, who trail Eintracht Frankfurt 2-1 after the first leg of their Europa League semi-final.
Tottenham host Leicester, who have it all to play for next week in the last four of their Europa Conference League tie after a 1-1 draw with Roma in Thursday’s first leg.
Fixtures (all times GMT)
Newcastle v Liverpool (1130), Southampton v Crystal Palace, Aston Villa v Norwich, Wolves v Brighton, Watford v Burnley (all 1400), Leeds v Manchester City (1630)
Everton v Chelsea, Tottenham v Leicester (both 1300), West Ham v Arsenal (1530)
Manchester United v Brentford (1900)