"Racing Club de Lens announces that Yannick Cahuzac has been relieved of his duties as head coach of the first team," the Ligue 1 club said in a statement.
The Como rout, which equalled the heaviest defeat in the competition's history, proved a breaking point. It came sandwiched between two domestic losses: 1-0 to local rivals Lille, then 2-1 to Olympique de Marseille on Sunday.
Against Marseille, Lens conceded early through a glaring error while their fans unfurled a banner reading: "You are the shame of 120 years of history."
The collapse is a stark reversal for a club that won the French Cup and finished runners-up to Paris Saint-Germain in Ligue 1 last season.
Cahuzac is the club's second manager to be dismissed this season. Dino Toppmoeller took over in the close season from Pierre Sage, who left for Crystal Palace, but was dismissed in September after only six matches, despite a 1-0 win over PSG in the Trophee des Champions.
Cahuzac, Toppmoeller's assistant, stepped up but lasted less than two months, winning three of his nine games and losing the other six in all competitions.
Lens sit 11th in Ligue 1 with 13 points and 33rd in the Champions League with three. They host Toulouse next week, looking to stop the slide.
