BACKGROUND: Nirmatrelvir/ritonavir, remdesivir, and molnupiravir are recommended antiviral therapies for non-severe COVID-19 patients at high risk of disease progression. This study evaluated the real-world effectiveness and economic impact of these three antiviral regimens in Thailand. METHODS: This retrospective observational study was conducted at Siriraj Hospital, Thailand. Eligible patients were ambulatory adults (≥15 years old) with non-severe COVID-19 infection, presenting ≥1 risk factor for disease progression, and receiving ≥1 dose of nirmatrelvir/ritonavir, remdesivir, or molnupiravir within 5 days of symptom onset. Subsequently, an economic analysis was performed using data from this study and landmark clinical trials. FINDINGS: During the study period (March-August 2022), there were 374 eligible patients: 104 patients (30.0 %), 114 patients (33.0 %), and 127 patients (37.0 %) received nirmatrelvir/ritonavir, remdesivir, and molnupiravir, respectively. The unfavorable clinical outcomes were significantly higher in the remdesivir group (12.28 %), compared to the nirmatrelvir/ritonavir group (2.88 %), and the molnupiravir group (4.72 %) by pairwise comparison (p-value<0.001). After adjusting for significant comorbidities, no statistically significant difference in unfavorable clinical outcomes was observed among these comparison groups. Economic analysis utilizing the effectiveness of landmark trials under Thai economic data indicated that remdesivir was the preferred option over the other two antivirals. Nirmatrelvir/ritonavir would become the dominant option over remdesivir if its price were to decrease to $108.157 or less per treatment course. INTERPRETATION: Compared to other countries, our study found higher unfavorable outcomes in vaccinated individuals, but lower than previous Thai data. Treatment effects were similar across groups. Our economic analysis favored remdesivir.