Background: COVID-19 is an infectious disease caused by SARS-CoV-2 and can lead to acute respiratory distress. Objective: We aimed to investigate the association between COVID-19 severity and serum apelin-17 and inflammatory mediator levels. Method: This cross-sectional study was conducted on patients with COVID-19. COVID-19 infection was confirmed by the RT-PCR test. The patients' data were extracted from their records. Venous blood samples were obtained from the patients to investigate the serum levels of apelin-17 and inflammatory mediators. Results: Results: Eighty-six COVID-19 patients were studied. The mean age of the participants was 55.56±14.88, and 43 (50%) were male. Clinical symptoms were dyspnea 77.6%, fever 52.3%, cough 48.8%, gastrointestinal symptoms 15.1%, and chest pain 7%. The overall mortality rate was 7%. No significant relationship was found between serum apelin-17 levels and COVID-19 severity (P= 0.48). However, there was a significant and direct relationship between COVID-19 severity and serum levels of CRP (P= 0.038) and D-dimer (P= 0.029). Conclusion: Serum apelin-17 levels were higher in recovered patients than those who died (4.90 vs. 3.19). Moreover, serum apelin-17 levels were higher in the patients admitted to the general ward than those admitted to the ICU (5.15 vs. 3.98). The difference was not statistically significant. However, there was a significant and direct relationship between serum apelin-17 levels and lymphocyte count (P= 0.022). Moreover, there was a significant and inverse relationship between lymphocyte count and COVID-19 severity (P= 0.004). Therefore, it can be interpreted that COVID-19 severity may decrease with an increase in serum apelin-17 levels. Therefore, to prove this hypothesis, a study with larger sample size is recommended.