A seventh defeat in nine games further damaged United's chances of Champions League qualification, but they could still make the top four with Tottenham, Chelsea and Arsenal also faltering.
Here, AFP Sports looks at what remains in the run-in for all of the top six.
Manchester City - 89 points
The title remains in City's hands thanks to a run of 11 straight Premier League wins and victory at Old Trafford on Wednesday was a huge step towards becoming the first side to retain the Premier League in a decade.
A trip to Burnley on Sunday is followed by the visit of Leicester to the Etihad before City end the season at relegation-threatened Brighton.
City's Champions League elimination means they will have a full week to prepare for their final two league games.
Liverpool - 88 points
A run of nine consecutive wins in all competitions has helped keep Jurgen Klopp's men stay on City's coattails and in position to pounce should the champions suffer an unexpected stumble in their remaining three games.
A first top-flight title in 29 years was described by Klopp as the "holy grail" after Sunday's 2-0 win at Cardiff and even if they fall short, it has been a historic campaign for the Reds.
Liverpool already have more points than ever before in the Premier League era and they should comfortably add three more when relegated Huddersfield visit Anfield on Friday.
A tricky trip to Newcastle sandwiched between two Champions League semi-final clashes with Barcelona is a potential banana skin before they host Wolves on the final day of the season.
Tottenham - 70 points
Spurs could still seal their place in the Champions League next season by winning the competition as they face Ajax in the last four.
However, Mauricio Pochettino's men are on course to seal a fourth straight season of Champions League football as they sit third, four points ahead of fifth-placed Arsenal.
Tottenham have won all four games since moving into the club's new stadium and appear to have the easiest run-in of the top four contenders as they host West Ham and Everton either side of a trip to Bournemouth.
Chelsea - 67 points
Chelsea missed a huge opportunity with a 2-2 draw at home to Burnley on Monday after a weekend during which Tottenham, Arsenal and United all lost.
However, a meeting against United at Old Trafford offers the chance for immediate redemption and to realistically kill off the Red Devils' chances of the top four.
Chelsea also have the safety net of Champions League qualification should they win the Europa League, where the face Eintracht Frankfurt in the semi-finals.
After their visit to Manchester, Maurizio Sarri's men host Watford and visit Leicester in their final two league games, both of whom are involved in the race for seventh and potential Europa League football next season.
Arsenal - 66 points
The Gunners have suffered shocking back-to-back defeats to Crystal Palace and Wolves at the worst time to fall back outside the top four.
Unai Emery's men have won just six of their 17 Premier League away games and face two more difficult road trips to Leicester and Burnley either side of Brighton's visit to the Emirates.
However, like Chelsea, Arsenal could end up relying on the Europa League as a route into the Champions League as they face Emery's old club Valencia in the last four.
Manchester United - 64 points
Despite a dreadful run of seven defeats in nine games, capped by another derby lesson at the hands of City, United remain in the hunt for a top-four finish.
However, Ole Gunnar Solskjaer must summon a response when Chelsea visit Old Trafford on Sunday if the Norwegian is to dismiss growing doubts that his superiors jumped the gun in handing him the job on a permanent basis last month.