Manchester United face Chelsea on Sunday with interim manager Ruud van Nistelrooy at the helm while faltering Arsenal face a potentially tricky trip to Newcastle.
Top-four hopefuls Tottenham and Aston Villa go head to head as the three teams in the relegation zone – Ipswich, Wolves and Southampton – each look for their first win of the season.
AFP Sport picks out some of the key talking points ahead of the weekend action.
MAN UTD CRAVE VAN NISTELROOY LIFT
The current Manchester United side are a pale shadow of the team Ruud van Nistelrooy played for under the leadership of Alex Ferguson.
The former striker, in temporary charge after Erik ten Hag's sacking earlier this week, will be in the dugout against Chelsea, looking to build on the club's 5-2 League Cup win against Leicester in midweek.
United, 14th in the Premier League and with Sporting Lisbon's Ruben Amorim widely expected to soon take over as coach, could potentially fall to 16th if results go against them this weekend.
Chelsea are riding high in Enzo Maresca's first season in charge, just one point off the top four, and will be well rested after the Italian changed his whole team for their midweek League Cup defeat against Newcastle.
But Van Nistelrooy, who spent five years at United as a player from 2001 to 2006, will be hoping he can inspire his charges during his brief spell in the Old Trafford spotlight.
ARSENAL RISK SLIPPING OFF THE PACE
Injury-hit Arsenal suffered the frustration of conceding a late equaliser against Liverpool last week, following their shock defeat at Bournemouth.
If they lose at St James' Park on Saturday, they could find themselves a daunting eight points behind champions City by the end of the day.
Mikel Arteta's men have pushed City all the way in the past two seasons and know they cannot afford to fall off the pace, with Liverpool also riding high.
The Gunners' 3-0 League Cup win against Preston in midweek gave them a lift ahead of tough games against Newcastle, Inter Milan and Chelsea, with Gabriel Jesus scoring his first goal since January.
Although any match at St James' Park is potentially daunting, Newcastle are more of a threat on paper than on the pitch at the moment following a run of five league games without a win.
INCONSISTENT SPURS
Tottenham are a conundrum – capable of scintillating attacking football but frustratingly fragile.
Ange Postecoglou knows his inconsistent team must put a run of results together if they are to challenge for the top four, which they missed out on last season.
Spurs have enjoyed big wins against Everton, Manchester United and West Ham but they have already suffered four defeats in their nine Premier League matches so far.
Spurs, who have won eight of their past 10 games in all competitions, suffered a shock 1-0 defeat at Crystal Palace last week before a morale-boosting League Cup win against Manchester City in midweek.
Postecoglou will be desperate to have Son Heung-min fighting fit after the South Korean missed three of the past four league games.
Unai Emery's Villa have dazzled in the Champions League and have made a strong start to their Premier League season, sitting fourth in the table, level on points with Arsenal.
They have drawn three of their past four league games to lose ground on the leaders, but have won on their past two visits to the Tottenham Hotspur Stadium and boast significant firepower with Ollie Watkins and Jhon Duran in the ranks.