Since the emergence of the first case of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), the viral genome has constantly undergone rapid mutations for better adaptation in the host system. These newer mutations have given rise to several lineages/ variants of the virus that have resulted in high transmission and virulence rates compared to the previously circulating variants. Owing to this, the overall caseload and related mortality have tremendously increased globally to > 233 million infections and > 4.7 million deaths as of Sept. 28th, 2021. SARS-CoV-2, Spike (S) protein binds to host cells by recognizing human angiotensin-converting enzyme 2 (hACE2) receptor. The viral S protein contains S1 and S2 domains that constitute the binding and fusion machinery, respectively. Structural analysis of viral S protein reveals that the virus undergoes conformational flexibility and dynamicity to interact with the hACE2 receptor. The SARS-CoV-2 variants and mutations might be associated with affecting the conformational plasticity of S protein, potentially linked to its altered affinity, infectivity, and immunogenicity. This review focuses on the current circulating variants of SARS-CoV-2 and the structure-function analysis of key S protein mutations linked with increased affinity, higher infectivity, enhanced transmission rates, and immune escape against this infection.