Mohamed Salah has gone for up to a month, costing Liverpool its all-time leading goal-scorer in the Premier League.
Manchester United has lost its most potent attacking force in Bryan Mbeumo, along with two more key figures.
They're nothing compared to Sunderland, a promoted team punching above its weight in England's top flight. It has been decimated by the loss of six players.
The Africa Cup of Nations is taking a toll on the Premier League, with some of its biggest stars heading off to the tournament situated right in the middle of the season, according to The AP news.
It is unfortunate that AFCON can be cast as a nuisance for many clubs in Europe — though international soccer in general can be viewed like that when pitted against club ambitions of winning titles. But at least the World Cup, European Championship or Copa America are staged during the offseason of Europe's top leagues.
AFCON is traditionally held in January-February but has been brought forward this year — from Sunday to Jan. 18 — meaning less disruption for leagues in Spain, Germany and France, which have winter breaks of varying periods in December-January.
The Premier League, however, plays through the Christmas and New Year holidays, with the added strain of the FA Cup thrown into one of the busiest periods of the campaign.
The likes of Liverpool and United should have deep enough squads to cope with the loss of key players such as Salah and Mbeumo. But it could have a major impact on Sunderland, which is just two points off the top four after an outstanding start to the season.
Arthur Masuaku, Noah Sadiki, Bertrand Traore, Habib Diarra, Chemsdine Talbi and Reinildo Mandava are all taking part in the Africa Cup in Morocco.
Sunderland is an outlier with so many going to the tournament but for Crystal Palace the loss of just one player — Ismaila Sarr — is potentially significant, given his importance to the team. Likewise, Brighton is losing key midfielder Carlos Baleba.
Burnley, second to bottom in the standings, is losing three players and so is Fulham.
Notably, at the top of the table, Arsenal has no players in the AFCON, likewise title-challenging Aston Villa and Chelsea, which could be telling over the next month.
Premier League players going to AFCON Brentford: Dango Ouattara (Burkina Faso), Frank Onyeka (Nigeria)
Brighton: Carlos Baleba (Cameroon)
Burnley: Axel Tuanzebe (DR Congo), Hannibal Mejbri (Tunisia), Lyle Foster (South Africa)
Crystal Palace: Ismaila Sarr (Senegal)
Everton: Idrissa Gana Gueye (Senegal), Iliman Ndiaye (Senegal)
Fulham: Calvin Bassey (Nigeria), Samuel Chukwueze (Nigeria), Alex Iwobi (Nigeria)
Liverpool: Mohamed Salah (Egypt)
Manchester City: Rayan Ait-Nouri (Algeria), Omar Marmoush (Egypt)
Manchester United: Bryan Mbeumo (Cameroon), Amad Diallo (Ivory Coast), Noussair Mazraoui (Morocco)
Nottingham Forest: Willy Boly (Ivory Coast), Ibrahim Sangare (Ivory Coast)
Sunderland: Arthur Masuaku (DR Congo), Noah Sadiki (DR Congo), Bertrand Traore (Burkina Faso), Habib Diarra (Senegal), Chemsdine Talbi (Morocco), Reinildo Mandava (Mozambique)
Tottenham Hotspur: Yves Bissouma (Mali), Pape Matar Sarr (Senegal)
West Ham United: Aaron Wan-Bissaka (DR Congo), El Hadji Malik Diouf (Senegal)
Wolverhampton Wanderers: Emmanuel Agbadou (Ivory Coast), Tawanda Chirewa (Zimbabwe)
Key matchups On Saturday, first-place Arsenal travels to Everton, while City in second is at home against West Ham. Liverpool will look to win back-to-back league games for the first time since September when the defending champion heads to Tottenham.
Aston Villa and United meet on Sunday.
Players to watch Hugo Ekitike has scored four goals in his last two league games. With Salah off to the AFCON, Liverpool's other forwards can establish themselves without the noise that has surrounded the Anfield icon in recent weeks when his future has been placed in doubt.
Out of action United States international Tyler Adams suffered suspected left knee MCL damage in Bournemouth's 4-4 draw with United on Monday. Chelsea forward Estevao has a small muscle issue, coach Enzo Maresca said. Everton was monitoring a potential hamstring complaint for Jack Grealish.
Off the field Expect more protests at last-place Wolves.
Bottom of the standings and looking certain to be relegated, Wolves will equal Sheffield United's 2020-21 record of 17 games without a win from the start of a Premier League season if they fail to beat Brentford at home on Saturday.
There were protests at Wolves' last home match against Manchester United this month and, despite a spirited performance at Arsenal last week, Rob Edwards' team is 14 points adrift of safety.
