SARS-CoV-2 infection induces non-physiological syncytia when its spike fusogenic protein on the surface of the host cells interacts with the ACE2 receptor on adjacent cells. Spike-induced syncytia are beneficial for virus replication, transmission, and immune evasion, and contribute to the progression of COVID-19. In this review, we highlight the properties of viral fusion proteins, mainly the SARS-CoV-2 spike, and the involvement of the host factors in the fusion process. We also highlight the possible use of anti-fusogenic factors as an antiviral for the development of therapeutics against newly emerging SARS-CoV-2 variants and how the fusogenic property of the spike could be exploited for biomedical applications.