Around the world, the COVID-19 pandemic has presented many difficulties, and acute respiratory distress syndrome (ARDS) has become a major worry. The antiviral and anti-inflammatory characteristics of methylene blue (MB) have garnered interest for potential medicinal applications. The object of the current study is to assess the effect of orally administered MB on the treatment of ARDS associated with COVID-19. A randomized clinical study was carried out on 122 hospitalized patients who had ARDS related to COVID-19. Patients who met the eligibility requirements were randomized at random to either the control group (CG) (n = 60) or the intervention group (IG) (n = 62). Standard treatments were administered to both groups, with the addition of oral MB to the IG. Clinical outcomes, including SpO2 levels, CRP levels were assessed on the third and fifth days. Additionally, at the time of discharge, patients' assessments were made in terms of APACHE II scores, SOFA scores, LDH and CRP levels, SpO2, and respiratory rate in comparison to the day prior to the intervention. Patients were followed for mortality outcomes at one month and three months after the intervention. Significant changes were observed in SpO2 levels over time (P < 0.001) and between groups (P = 0.022), with higher levels in the MB-treated group. The interaction between time and group (P = 0.019) indicated a stronger increase in SpO2 in the IG, with the IG's SpO2 level increasing by 6.42%. Furthermore, CRP levels showed significant changes over time (P < 0.001), but not between groups (P = 0.092). However, the interaction between group and CRP change over time (P = 0.019) suggested a distinct pattern of CRP decrease in the IG. Significant improvement in RR, SpO2, CRP, and APACHE II score were found according to discharge results. However, in terms of SpO2 and the APACHE II score, this improvement was noteworthy for IG. The length of hospitalization and mortality rates at one- and three-month follow-ups did not differ significantly. Oral administration of MB demonstrated positive effects on improving SpO2 levels and reducing inflammatory markers in COVID-19-related ARDS patients. Despite no significant impact on survival rates or hospitalization length, the study supports the potential efficacy of MB as an alternative treatment for COVID-19 ARDS. This study was registered with the Iranian Registry of Clinical Trials ( http://www.irct.ir ) under the registration code IRCT20200409047007N2 on 11/29/2021.