The severity of COVID-19 is a result of the complex interplay between various branches of the immune system. However, our understanding of the role of neutralizing antibodies and the activation of cellular immune response in COVID-19 pathogenesis remains limited. In this study, we investigated neutralizing antibodies in patients with mild, moderate, and severe COVID-19, analyzing their cross-reactivity with the Wuhan and Omicron variants. We also assessed the activation of the immune response by measuring serum cytokines in patients with mild, moderate, and severe COVID-19. Our findings suggest the early activation of neutralizing antibodies in moderate COVID-19 compared to mild cases. We also observed a strong correlation between the cross-reactivity of neutralizing antibodies to the Omicron and Wuhan variants and the severity of the disease. In addition, we found that Th1 lymphocyte activation was present in mild and moderate cases, while inflammasomes and Th17 lymphocytes were activated in severe COVID-19. In conclusion, our data indicate that the early activation of neutralizing antibodies is evident in moderate COVID-19, and there is a strong correlation between the cross-reactivity of neutralizing antibodies and the severity of the disease. Our findings suggest that the Th1 immune response may play a protective role, while inflammasome and Th17 activation may be involved in severe COVID-19.