Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 that can have detrimental effects on multiple organs and accelerate patient mortality. This study, which encompassed 130 confirmed COVID-19 patients who were assessed at three different time points (i.e., 3, 7, and 12 days) after the onset of symptoms, investigated interleukin-6 (IL-6) enhancement induced by a viral nucleocapsid (N) protein from a myeloid cell line. Disease severity was categorized as mild, moderate, or severe. The severe cases were characterized as having significant elevations in serum IL-6, C-reactive protein, D-dimer, ferritin, creatinine, leukocytes, and neutrophil-to-lymphocyte ratio and decreased hemoglobin, hematocrit, and albumin levels compared with mild and moderate cases. To evaluate IL-6-inducing activity, heat-inactivated sera from these patients were incubated with and without the N protein. The findings showed a progressive increase in IL-6 production in severe cases upon N protein stimulation. There was a strong correlation between anti-N antibodies and levels of IL-6 secreted by myeloid cells in the presence of N protein and sera, indicating the crucial role that the anti-N antibody plays in inducing IL-6 production. Uncontrolled IL-6 production played a pivotal role in disease pathogenesis, exacerbating both disease severity and mortality. Efficiently targeting the N protein could potentially be employed as a therapeutic strategy for regulating the immune response and alleviating inflammation in severe cases.