BACKGROUND Coronavirus disease 2019 (COVID-19) is a global pandemic putting the population at a high risk of infection-related health hazards, mortality and a potential failure of proper medical therapies. Therefore, it is necessary to evaluate the potential use of the existing drugs that could be used as options for the medical management of COVID-19 patients. AIM To evaluate the role of the H 2 receptor blocker “famotidine” in COVID-19 illness. METHODS This study was done on seriously ill COVID-19 patients admitted to the intensive care unit (ICU) from different institutes in Bangladesh. Patients were divided into famotidine treatment group “A” (famotidine 40 mg to 60 mg oral formulation every 8 h with other treatment as given), and control group “B” (treatment as given). National early warning score (NEWS)-2, and sequential organ failure assessment day-1 score was calculated to evaluate the outcome. Outcomes were evaluated by the time required for clinical improvement, characterized as duration required from enrollment to the achievement of NEWS-2 of ≤ 2 maintained for 24 h; time to symptomatic recovery, defined as the duration in days (from randomization) required for the recovery of the COVID-19 symptoms; mortality rate; duration of ICU and hospital stay; total period of hospitalization; the rate of supplementary oxygen requirement; the computed tomography (CT) chest recovery (%), the time required for the viral clearance and “NEWS-2” on discharge. RESULTS A total of 208 patients were enrolled in this study with 104 patients in each group. The famotidine treatment group had comparatively better recovery of 75% and a low mortality of 25% than the control with a recovery of 70% and a mortality of 30%. Duration of clinical improvement (group A 9.53 d, group B 14.21 d); hospitalization period among the recovered patients (group A 13.04 d, group B 16.31 d), pulmonary improvement in chest CT (group A 21.7%, group B 13.2%), and the time for viral clearance (group A 20.7 d, group B 23.8 d) were found to be statistically significant P ≤ 0.05. However, the Kaplan Meier survival test was not significant among the two study groups, P = 0.989. CONCLUSION According to our study, treatment with famotidine achieved a better clinical outcome compared to the control group in severe COVID-19 illness, although no significant survival benefit was found.