Leicester have had to cede Riyad Mahrez, Islam Slimani and Daniel Amartey.
Manchester United and Liverpool have each lost an important player, but in the Premier League it is Leicester City for whom the Africa Cup of Nations is the biggest inconvenience.
While United centre-back Eric Bailly has been called up by the Ivory Coast and Liverpool have lost Senegalese flier Sadio Mane, Leicester have had to cede Riyad Mahrez, Islam Slimani and Daniel Amartey.
Fifteenth in the table, Leicester are fighting to avoid being dragged into a relegation dogfight and left-back Christian Fuchs says it is a chance for the squad's fringe players to prove their worth.
"These are very essential players for us," Fuchs told local newspaper the Leicester Mercury.
"We can talk about how it will hurt us and make us weaker, but it is the time for the other guys to step up and show they are needed."
Mahrez, 25, was named African Player of the Year last week for his starring role in Leicester's 5,000-1 title triumph, having also been named England's Players' Player of the Year for last season.
Although he has gone off the boil this term, the quicksilver Algerian winger remains a key figure for Leicester and with seven goals in all competitions he is the club's leading scorer.
He is joined in Algeria's squad by Slimani, who has scored six goals since his club-record £29 million ($35.3 million, 33.4 million euros) switch from Sporting Lisbon.
Completing the triumvirate is Ghana midfielder Amartey, but his compatriot Jeff Schlupp remains at Leicester manager Claudio Ranieri's disposal after missing out on selection by Avram Grant.
While the three absentees will be missed, Ranieri can count himself lucky that Nigeria are not among the 16 teams assembled in Gabon.
Nigerian forward Ahmed Musa scored twice as Leicester came from behind to beat Everton 2-1 in the FA Cup on Saturday and his international team-mate Wilfred Ndidi has just arrived in a £15 million move from Genk.
Bailly's departure leaves Manchester United light in central defence, particularly with Marcos Rojo having sustained a muscular injury during Saturday's 4-0 FA Cup win over Reading.
Mane will be missed by Liverpool, having scored nine goals since arriving from Southampton to help Jurgen Klopp's side climb to second place in the table.
Chelsea, the league leaders, have learnt to rue the Africa Cup of Nations in the past, having seen stars such as Didier Drogba, Michael Essien and Salomon Kalou wrenched from their grasp mid-season.
But with Nigerian Victor Moses the only African player in Antonio Conte's first-team squad, they will be completely unscathed by the latest edition of the tournament.
Yaya Toure having retired from Ivory Coast duty and Kelechi Iheanacho's Nigeria having not qualified, Manchester City are in the same boat.
Kenya's non-qualification means Tottenham Hotspur will retain the services of midfield destroyer Victor Wanyama and Arsenal have lost only Egyptian reserve Mohamed Elneny.
Everton have also released only one player, but Senegalese midfielder Idrissa Gueye has become a vital cog since his close-season switch from Aston Villa.
Crystal Palace manager Sam Allardyce will be lamenting in-form winger Wilfried Zaha's decision to switch allegiances from England to the Ivory Coast, particularly having also lost Bakary Sako to Mali.
Stoke City have lost three players -- Wilfried Bony (Ivory Coast), Ramadan Sobhi (Egypt) and Mame Biram Diouf (Senegal) -- and West Ham United must do without Cheikhou Kouyate (Senegal) and Andre Ayew (Ghana).
The tournament could have weighty consequences at the foot of the table.
Sunderland will miss Lamine Kone (Ivory Coast), Didier N'Dong (Gabon) and Wahbi Khazri (Tunisia), while bottom club Hull City are now without Ahmed Elmohamady (Egypt) and Dieumerci Mbokani (DR Congo).
"It will put us at risk as far as numbers in our squad go, but some of these players could be back in three weeks," said Sunderland manager David Moyes.
"We just don't know how long they will be in the tournament."