The 27-year-old, who was absent from last week's 22-16 defeat against Leicester Tigers due to the birth of his child, will take his place at scrum-half as the Quins look to kick off their European Rugby Champions Cup campaign with a win.
England international Care has made 167 appearances for Harlequins since joining the club in 2006.
Harlequins: Brown; Yarde, Hopper, Lowe, Tikoirotuma; Evans, Care; Marler, Ward, Collier, Matthews, Robson, Wallace, Robshaw, Easter
Replacements: Buchanan, Lambert, Sinckler, Twomey, Trayfoot, Dickson, Turner-Hall, Lindsay- Hague
Castres: Palis; Evans, Tuatara, Combezou, Grosso; Tales, Kockott; Taumoepeau, Mach, Montes, Gray, Faasalele, Diarra, Whetton, Bornman
Replacements: Rallier, Lazar, Faanunu, Babillot, Samson, Dumora, Cabannes, Garcia