Liverpool can move three points clear of current leaders Arsenal and four ahead of City if they beat Brighton at Anfield earlier in the day.
At the other end of the table, Nottingham Forest are in action for the first time since a four-point penalty for breaching financial rules plunged them into the relegation zone.
AFP Sport looks at three talking points as the English top flight returns after the international break.
Can Arsenal storm Man City fortress?
Arsenal became just the fourth team to win each of their first eight Premier League games of a calendar year when they beat Brentford in early March - the previous three clubs to do that all went on to win the title.
The Gunners' record against City in the Premier League is dire, with 12 defeats in their past 13 games, though their lone victory came at the Emirates in October, courtesy of Gabriel Martinelli's deflected strike.
"It feels like a big win," said Arsenal manager Mikel Arteta. "It is a special one."
Arteta's men look a more battle-hardened force than last year, when they stumbled at the end of the season, opening the door for City to cruise past to a third straight title.
Repeating the feat at the Etihad is a different order of magnitude.
City are unbeaten in their last 38 home games in all competitions. Brentford were the last visiting team to leave with a win and that was in November 2022.
If Arsenal do manage to complete their first league double over City since 2007/08, it could be the boost they need to get them over the line.
Liverpool focus on league
Liverpool's exit from the FA Cup at the hands of Manchester United ended their push for a trophy quadruple in Jurgen Klopp's final season at Anfield.
The German manager, who has kept his team on track despite a deep injury crisis, brushed off any idea of a negative psychological impact after the 4-3 defeat at Old Trafford.
"In general, the team is in an outstanding situation in the moment," he said. "That we got through all of these different, difficult situations is absolutely exceptional."
Liverpool trail league leaders Arsenal on goal difference and will hope the Gunners and City cancel each other out in Manchester.
Brighton have drawn their past two matches at Anfield but they have not won consecutive league games since September and Liverpool will be confident they have the firepower to win as their injury crisis eases.
Forest seek lift after points penalty
Nottingham Forest's draw against Luton on March 16th left them three points clear of the relegation zone but they are now looking up at Rob Edwards' team after their punishment for breaking profit and sustainability (PSR) rules.
Forest lodged an appeal against the sanction as they prepare to host Crystal Palace on Saturday.
Forest are the second top-flight team to be penalised for PSR breaches this season after Everton were hit with a 10-point penalty in November, which was reduced to six on appeal.
The punishments are creating an air of uncertainty at the basement of the Premier League, adding to the normal pressures of a relegation battle.
Everton, four points above Forest, could face further punishment after being charged with a second breach of the rules.
Forest are in deep trouble in just their second season back in the top flight, but they can take heart that all the sides around them are struggling as well.
