Inflammation has a crucial role in COVID-19 pathogenesis, and previous studies have proposed an important function of IL-6 during inflammation. On the other hand, IL-6 levels and inflammation might be associated with hypoxia-inducible factor-1α (HIF-1α). Thus, due to the possible role of HIF-1α in inflammation and COVID-19 pathogenesis, we aimed to investigate the levels of HIF-1α and its correlation with inflammatory parameters (IL-6 and CRP) and D-dimer. In this case-control study, 84 patients (54 patients hospitalized in the ICU and 30 individuals as outpatient subjects) were included as the case group, and 50 healthy subjects were included as the control group. The levels of D-dimer, CRP, IL-6 (interleukin 6) and HIF-1α were assessed in all studied groups. The results of the present investigation showed that the levels of D-dimer, CRP and IL-6 were significantly increased in COVID-19 patients compared to healthy individuals. On the other hand, the level of HIF-1α significantly decreased in COVID-19 patients. In addition, there was a significant correlation between IL-6 and CRP and D-dimer, while HIF-1α was indirectly correlated with IL-6, CRP and D-dimer. Ultimately, our data indicated that the levels of CRP, D-dimer, IL-6 and HIF-1α were significantly different between ICU patients and the outpatient group with healthy individuals. Based on the study results, inflammation plays a crucial role in COVID-19 pathogenesis, and low HIF-1α is a consequence of inflammation due to COVID-19 infection and might have a protective role in COVID-19.