Introduction As the rst randomized clinical trial, this study evaluated the effect of Famotidine on the improvement of outcomes of hospitalized patients with COVID-19. Method This phase III randomized clinical trial was designed with two parallel arms, placebo-controlled, singleblind, and concealed allocation, and recruited 20 patients. Oral Famotidine 160 mg four times a day was given to patients until the discharge day or for a maximum of 14 days. Patients' temperature, respiration rate, oxygen saturation, lung in ltration, lactate dehydrogenase (LDH) level and complete blood count (CBC) were measured at the baseline (before the intervention) and on day 14 after the intervention or on discharge day. Length of stay in the hospital and length of stay in the ICU were also measured as secondary outcomes of the study. Results The results showed a signi cant decrease in LDH (P = 0.01), mean WBC (P = 0.04) and length of stay (P = 0.04) of patients with COVID-19 in the group treated with Famotidine compared to the control group. There was also a signi cant increase in oxygen saturation (P = 0.01) in the group treated with Famotidine compared to the control group. Cough improvement was also higher in the oral Famotidine group compared to the control group (P = 0.02). Conclusion This was the rst clinical trial on the effect of Famotidine on the improvement of hospitalized COVID-19 patients, which indicated that high-dose Famotidine improves patients' clinical signs and reduces the severity of the disease and duration of hospitalization.