Rationale: Coronavirus disease 2019 (COVID-19) leads to hospitalization and death, especially in elderly and those with comorbidities. There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. Objective: In this observational study on acutely symptomatic outpatient COVID-19 cases, we investigated the effects of spironolactone and sitagliptin on the outcomes of the disease. Methods: This prospective cohort study was conducted at Shiraz University of Medical Sciences Clinics during the fifth wave of the COVID-19 pandemic between July 2021 and September 2021. We followed mild to moderate symptomatic COVID-19 patients, who were treated with either combination (spironolactone 100 mg daily and sitagliptin 100 mg daily) or standard (steroid, antiviral and/or supportive care) therapy up to 30 days. Our primary outcome was hospitalization rate. The secondary outcomes included ER visit, duration of disease, and complications, such as hypoglycemia, low blood pressure or altered mental status. Results: Of the 206 patients referred to clinics, 103 received standard therapy and 103 treated with combination therapy. There were no significant differences in baseline characteristics, except for slightly higher clinical score in control group (6.92 ± 4.01 control, 4.87 ± 2.92 combination; P <0.0001). Treatment with combination therapy was associated with lower admission rate (5.8% combination, 22.3% control; P = 0.0011), ER visits (7.8% combination, 23.3% control; P = 0.0021) and average duration of symptoms (6.67 ± 2.30 days combination, 18.71 ± 6.49 days control; P =<0.0001). Conclusion: In this prospective cohort study of acutely ill outpatients with COVID-19, the combination of sitagliptin and spironolactone reduced duration of COVID infection and hospital visits better than standard therapeutic approaches. The effects of combination of sitagliptin and spironolactone in COVID-19 patients should be further verified in a double blind, randomized, placebo-controlled trial. Iranian Registry of Clinical Trials: IRCT registration number: IRCT20201003048904N2, Registration date: December 10, 2020.