Background and Objectives <p>To better inform clinical and public health decision-making on the use of antiviral drugs for mild/moderate SARS-CoV-2 infection in Hong Kong, we sought to assess effectiveness of the approved nirmatrelvir/ritonavir and molnupiravir treatment regimens.</p> Methods <p>We conducted a cohort study of patients aged 18–64 years with laboratory-confirmed SARS-CoV-2 infection in Hong Kong between April 2022 and January 2023. We utilised a conditional logistic regression model with a 5-strata propensity score-matched analysis adjusted for potential confounders such as age, sex, SARS-CoV-2 vaccination status, and chronic conditions. The outcomes were disease progression (development/worsening of clinical symptoms/conditions), intensive care unit (ICU) admission among hospitalised persons, and mortality at 28 days (infection-related) and 90 days (all-cause) following the recommended 5-day treatment course commencing within 5 days of symptom onset or laboratory confirmation and excluding persons who had a contraindication for the drugs. Results were expressed as adjusted odds ratios with associated 95% confidence intervals.</p> Results <p>We included 206,418 individuals, of which 53% were symptomatic at infection confirmation. About 33.3% of the individuals were treated with nirmatrelvir/ritonavir whereas only about 6.1% were treated with molnupiravir. Compared with no treatment, treatment with either nirmatrelvir/ritonavir or molnupiravir was associated with significantly reduced odds of disease progression in patients aged 18–44 years [0.20 (0.09–0.42) and 0.10 (0.04–0.26), respectively] and patients aged 45–64 years [0.14 (0.10–0.20) and 0.19 (0.14–0.25), respectively]. Whereas mostly no significant associations were observed with these drugs for the other outcomes in patients aged 18–44 years, they were associated with significantly reduced odds of the outcomes in patients aged 45–64 years. There was no significant difference in the head-to-head comparison between nirmatrelvir/ritonavir and molnupiravir against all the outcomes in patients aged 18–44 years, and against ICU admission in patients aged 45–64 years, but compared with molnupiravir in those aged 45–64 years, nirmatrelvir/ritonavir was associated with significantly reduced odds of disease progression, SARS-CoV-2 infection-related mortality, and all-cause mortality [0.39 (0.22–0.70), 0.20 (0.10–0.38), and 0.33 (0.21–0.53), respectively]. We made these observations mostly irrespective of symptom status.</p> Conclusions <p>Nirmatrelvir/ritonavir and molnupiravir treatment regimens seemed effective against clinically relevant outcomes in patients aged 18–64 years with laboratory-confirmed SARS-CoV-2 infection in Hong Kong, particularly in those aged 45–64 years for whom nirmatrelvir/ritonavir seemed better than molnupiravir.</p>