BackgroundHydrogen/oxygen therapy contribute to ameliorate dyspnea and disease progression in patients with respiratory diseases. Therefore, we hypothesized that hydrogen/oxygen therapy for ordinary coronavirus disease 2019 (COVID-19) patients might reduce the length of hospitalization and increase hospital discharge rates.MethodsThis retrospective, propensity-score matched (PSM) case–control study included 180 patients hospitalized with COVID-19 from 3 centers. After assigned in 1:2 ratios by PSM, 33 patients received hydrogen/oxygen therapy and 55 patients received oxygen therapy included in this study. Primary endpoint was the length of hospitalization. Secondary endpoints were hospital discharge rates and oxygen saturation (SpO2). Vital signs and respiratory symptoms were also observed.ResultsFindings confirmed a significantly lower median length of hospitalization (HR = 1.91; 95% CIs, 1.25–2.92;p< 0.05) in the hydrogen/oxygen group (12 days; 95% CI, 9–15) versus the oxygen group (13 days; 95% CI, 11–20). The higher hospital discharge rates were observed in the hydrogen/oxygen group at 21 days (93.9% vs. 74.5%;p< 0.05) and 28 days (97.0% vs. 85.5%;p< 0.05) compared with the oxygen group, except for 14 days (69.7% vs. 56.4%). After 5-day therapy, patients in hydrogen/oxygen group exhibited a higher level of SpO2compared with that in the oxygen group (98.5%±0.56% vs. 97.8%±1.0%;p< 0.001). In subgroup analysis of patients received hydrogen/oxygen, patients aged < 55 years (p= 0.028) and without comorbidities (p= 0.002) exhibited a shorter hospitalization (median 10 days).ConclusionThis study indicated that hydrogen/oxygen might be a useful therapeutic medical gas to enhance SpO2and shorten length of hospitalization in patients with ordinary COVID-19. Younger patients or those without comorbidities are likely to benefit more from hydrogen/oxygen therapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12879-023-08424-4.