Apoptosis is a type of programmed cell death that plays a vital role in removing the redundant cells, damaged cells, or virally infected cells to help maintain homeostasis in tissues. There are three initiating pathways of apoptosis activation including the intrinsic via mitochondrial, extrinsic via death receptor, and perforin/granzyme pathway. Apoptosis is considered as a protective mechanism in the host but when this disordered program causes pathological outcomes. In SARS-CoV-2 virus infection, extrinsic and intrinsic pathways of apoptosis are associated with ORF3a and 7a proteins, respectively. Many studies showed that inappropriate apoptosis is involved in different pathogenicity and severity of COVID-19. Therefore, understanding apoptosis mechanism helps us to have new therapeutic strategies in the treatment of SARSCoV-2 virus infection and be able to decrease the damage caused by excessive immune responses.