Ruben Amorim takes charge of Manchester United for the first time in Sunday's trip to Ipswich, while Manchester City are aiming to snap a historic losing streak for Pep Guardiola against Tottenham.
Fourth takes on fifth in another of Saturday's eye-catching fixtures when Arsenal hope to kickstart their faltering title challenge at home to Nottingham Forest.
AFP Sport picks out some of the key talking points ahead of this weekend's action:
MAN UTD START AMORIM ERA
Manchester United fans have been made to wait three weeks for Ruben Amorim's arrival since he was confirmed as the successor to Erik ten Hag.
The Portuguese coach does not face a baptism of fire, but Ipswich are on a high ahead of the visit of the Red Devils after securing their first Premier League win for 22 years before the international break with a shock 2-1 victory at Tottenham.
Amorim has plenty of problems to solve at Old Trafford, but begins with United only four points adrift of the top four despite sitting down in 13th.
Ten Hag managed just one win from seven away games in all competitions this season and Amorim must find a quick tonic to that travel sickness if he is to make a positive first impression with the United fans.
United midfielder Bruno Fernandes is confident his compatriot will quickly make a positive connection with his new players.
"Obviously for me, what stands out is the connection he has with the (Sporting) players," Fernandes said.
"You see the way they say goodbye to him, the way they feel, they make him feel part of the team and how they treat him.
"So it shows that this is a great character and he's someone that gives his all to the players."
SLUMPING MAN CITY EYE REVIVAL
Across Manchester, champions City have lost four consecutive games for the first time in Pep Guardiola's glorious managerial career.
However, on Thursday Guardiola signed a two-year contract extension, ending speculation over his future and allowing the boss to focus on reviving his spluttering side.
The two-week hiatus for international football also came at the right time for Guardiola to reset as he looks for key players to return from a lengthy injury list.
Guardiola's men find themselves five points behind leaders Liverpool, who face bottom-of-the-table Southampton on Sunday, and can ill afford to drop any more points ahead of a daunting trip to Anfield next weekend.
This is the sixth time a team has been five points clear after 11 Premier League games, with the previous five all finishing as champions.
But City have trailed the leaders by more than five points at one stage in each of the last four seasons and still finished with the title.
ARSENAL SEARCH FOR ANSWERS
The Gunners have fallen nine points behind Liverpool after a run of three wins from their last nine league matches, including four without a victory prior to the visit of Forest.
Great expectation was placed upon Mikel Arteta's men to end a two-decade wait to win the league after finishing second to City in each of the last two seasons.
But Arsenal's season has been a story of needless red cards, injuries to key men and a lack of killer instinct in front of goal.
Arteta needs to find answers quickly if they are to remain in the title race.