Adiponectin is primarily known for its protective role in metabolic diseases, and it also possesses immunoregulatory properties. Elevated levels of adiponectin have been observed in various inflammatory diseases. However, studies investigating adiponectin levels in the serum of COVID-19 patients have yielded conflicting results. This study aimed to assess serum adiponectin levels in 26 healthy controls, as well as in 64 patients with moderate and 60 patients with severe COVID-19, to determine a potential association between serum adiponectin and the severity of COVID-19. Serum adiponectin levels in severe COVID-19 patients were significantly lower than in those with moderate disease and healthy controls, who exhibited similar serum adiponectin levels. Among patients with moderate disease, positive correlations were observed between serum adiponectin and C-reactive protein levels. Of note, serum adiponectin levels of severe COVID-19 cases were comparable between patients with and without dialysis or vasopressor therapy. Superinfection with bacteria did not exert a notable influence on serum adiponectin levels in patients with severe disease. Patients who were diagnosed with severe COVID-19 and vancomycin-resistant enterococci bacteremia showed a significant reduction in their serum adiponectin levels. An analysis conducted on the entire cohort, including both moderate and severe COVID-19 patients, showed that individuals who did not survive had lower serum adiponectin levels when compared to those who survived. In summary, this study highlights a decrease in serum adiponectin levels in severe COVID-19 cases, indicating the potential utility of adiponectin as an additional biomarker for monitoring disease severity in COVID-19 or critical illnesses in general.