Developing effective vaccines is necessary in combating new virus pandemics. For human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the induction of neutralizing antibodies (NAb) is important for vaccine protection; however, the exact mechanisms underlying protection require further study. Recent data emphasize that even Abs that do not exhibit neutralizing activity may contribute to immune defense by Ab Fc-mediated inhibition. Abs exhibiting this function may counter virus mutations, which are acquired to escape from NAbs, and therefore broaden the protective Ab response induced by vaccination. The steps leading to inhibition are complex. How can these functions be measured in vitro? What inhibitory assay is physiologically relevant at mimicking effective in vivo protection? This review provides a comprehensive update on the current knowledge gaps on the Ab Fc-mediated functions involved in HIV and SARS-CoV-2 protection. Understanding the inhibitory effects of these Abs is vital for designing the next generation of protective HIV and SARS-CoV-2 vaccines.