Inhaled nitric oxide (iNO) is used as rescue therapy in patients with refractory hypoxemia due to severe COVID-19 acute respiratory distress syndrome (ARDS) notwithstanding the recommendation against the use of this treatment. Yet, the effect of iNO on the clinical outcomes of critically ill COVID-19 patients with moderate-to-severe ARDS remains questionable. Therefore, this study examines the use of iNO in critically ill COVID-19 patients with moderate-to-severe ARDS. This multicenter, retrospective cohort analysis comprised critically ill adult patients with confirmed COVID-19 treated from March 01, 2020, to July 31, 2021. Eligible patients with moderate-to-severe ARDS were later classified into 2 groups based on inhaled nitric oxide (iNO) use during their ICU stay. The primary endpoint was the improvement in oxygenation parameters 24 h following iNO administration. Other results were considered secondary. Propensity score matching (1:2) was applied based on the predefined criteria. A total of 1,598 patients were screened, and 815 were enrolled based on the eligibility criteria. Among them, 210 patients were matched based on predetermined criteria. Oxygenation parameters (PaO2, FiO2 demand, P/F ratio, oxygenation index) were considerably improved 24 h after iNO delivery within a median of 6 days of ICU admission. However, the risk of 30-day and in-hospital mortality were found to be similar between the 2 groups (HR: 1.18; 95% CI: 0.77, 1.82; P=0.45 and HR: 1.40; 95% CI: 0.94, 2.11; P=0.10, respectively). On the other hand, ventilator-free days (VFDs) were significantly fewer, and ICU and hospital LOS were much longer in the iNO group. In addition, patients who received iNO had greater risks of acute kidney damage (AKI) (OR (95% CI): 2.35 (1.30, 4.26), P value = 0.005) and hospital/ventilator-acquired pneumonia (OR (95% CI): 3.2 (1.76, 5.83), P value = 0.001). While iNO rescue therapy is related to better oxygenation parameters, it is not associated with any mortality improvements in critically ill COVID-19 patients with moderate to severe ARDS. Additionally, the use of iNO is linked to increased risks of AKI and pneumonia, as well as longer LOS and fewer VFDs.