The Asian Cup kicks off on January 12 and will run until February 10, while the Africa Cup of Nations begins and ends a day later, meaning that those selected could miss up to a full month of club action.
That could mean as many as seven fixtures for some clubs across all competitions, and while the 40 Premier League players to have been called up to either AFCON or the Asian Cup will have their sights set firmly on leading their countries to glory, they will also no doubt have one eye on how their employers fare in their absence.
Of the 20 Premier League clubs, 17 will be missing at least one player during that spell, with Burnley, Manchester City and Newcastle United the only ones to still have their full complement during the tournaments.
By contrast, Nottingham Forest will be the worst-affected club with no fewer than six players heading to the Africa Cup of Nations - Ola Aina, Serge Aurier, Willy Boly, Cheikhou Kouyate, Moussa Niakhate and Ibrahim Sangare.
Brentford and Wolverhampton Wanderers will both be missing four players apiece, while Fulham, Manchester United and Tottenham Hotspur must make do without three players for up to a month.
Indeed, Spurs could lay claim to being the worst-affected of anyone in terms of quality, with key defensive midfield duo Yves Bissouma and Pape Matar Sarr heading to the Africa Cup of Nations and star man Son Heung-min travelling to the Asian Cup.
Man United will be without Sofyan Amrabat, Amad Diallo and Andre Onana, although they are hoping to delay the latter's departure to enable him to face Spurs on January 14.
Liverpool will also be without a couple of high-profile players, including arguably the biggest absentee of all as the in-form Mohamed Salah joins up with Egypt.
Wataru Endo links up with Japan having become an increasingly important part of Jurgen Klopp's league-leading side in recent weeks, leaving the Reds with two regular starters to replace for the next month.
Other notable names and key club players to be departing for international duty include the likes of Brighton & Hove Albion's Kaoru Mitoma, Chelsea's Nicolas Jackson, Everton's Idrissa Gueye, West Ham United's Mohammed Kudus and Wolves' Hwang Hee-chan.
Full club-by-club list of Premier League players called up for AFCON and Asian Cup
Arsenal: Mohamed Elneny (Egypt), Takehiro Tomiyasu (Japan)
Aston Villa: Bertrand Traore (Burkina Faso)
Bournemouth: Dango Ouattara (Burkina Faso), Antoine Semenyo (Ghana)
Brentford: Saman Ghoddos (Iran), Kim Ji-soo (South Korea), Frank Onyeka (Nigeria), Yoane Wissa (DR Congo)
Brighton: Simon Adingra (Ivory Coast), Kaoru Mitoma (Japan)
Burnley: None
Chelsea: Nicolas Jackson (Senegal)
Crystal Palace: Jordan Ayew (Ghana)
Everton: Idrissa Gueye (Senegal)
Fulham: Fode Ballo-Toure (Senegal), Calvin Bassey (Nigeria), Alex Iwobi (Nigeria)
Liverpool: Wataru Endo (Japan), Mohamed Salah (Egypt)
Luton Town: Issa Kabore (Burkina Faso)
Manchester United: Sofyan Amrabat (Morocco), Amad Diallo (Ivory Coast), Andre Onana (Cameroon)
Manchester City: None
Newcastle United: None
Nottingham Forest: Ola Aina (Nigeria), Serge Aurier (Ivory Coast), Willy Boly (Ivory Coast), Cheikhou Kouyate (Senegal), Moussa Niakhate (Senegal), Ibrahim Sangare (Ivory Coast)
Sheffield United: Yasser Larouci (Algeria), Anis Ben Slimane (Tunisia)
Tottenham: Yves Bissouma (Mali), Son Heung-min (South Korea), Pape Matar Sarr (Senegal)
West Ham: Nayef Aguerd (Morocco), Mohammed Kudus (Ghana)
Wolves: Hwang Hee-chan (South Korea), Justin Hubner (Indonesia), Rayan Ait-Nouri (Algeria), Boubacar Traore (Mali)