Background: As coronavirus disease 2019 (COVID-19) has evolved, patients increasingly present with milder disease, raising questions about optimal management of those hospitalized for other conditions, but found to have COVID-19 with high risk of progression. While these patients may traditionally be managed with a 3-day course of remdesivir (RDV) and nirmatrelvir/ritonavir (N/R) in the outpatient setting, these therapies have not been explicitly studied in a similar population, but in the inpatient setting. Objective: To evaluate outcomes with 3-day RDV versus 5-day N/R in high-risk hospitalized patients with mild COVID-19. Methods: This single-center, retrospective, propensity score-matched cohort study included hospitalized adult patients who were found to have mild COVID-19 between January 2023 and December 2023. Patients were grouped by treatment received, including 3-day RDV or 5-day N/R. Baseline characteristics and risk factors for disease progression were collected. Endpoints included incidence of disease progression, need for oxygen and respiratory support, length of stay, 30-day readmission, and mortality. Results: One-hundred and fifty patients were included in the analysis, with 75 in each group. Baseline characteristics between groups were similar. There was no significant difference in the rate of disease progression between the RDV and N/R group (19% vs 11%, respectively; P = 0.166). There was no difference in additional endpoints including hospital length of stay, 30-day readmission, or mortality. Conclusion: There was no significant difference in rates of disease progression or other outcomes among high-risk hospitalized adults with mild COVID-19 treated with RDV or N/R. Larger studies are needed to confirm these findings.