COVID-19 is a global health threat caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with a significant increase in morbidity and mortality. The present review discusses nuclear factor-kappa B (NF-κB) activation and its potential therapeutical role in treating COVID-19. COVID-19 pathogenesis, the major NF-κB pathways, and the involvement of NF-κB in SARS-CoV-2 have been detailed. Specifically, NF-κB activation and its impact on managing COVID-19 has been discussed. As a central player in the immune and inflammatory responses, modulating NF-κB activation could offer a strategic avenue for managing SARS-CoV-2 infection. Understanding the NF-κB pathway's role could aid in developing treatments against SARS-CoV-2. Further investigations into the intricacies of NF-κB activation are required to reveal effective therapeutic strategies for managing and combating the SARS-CoV-2 infection and COVID-19.