Background: Oseltamivir-resistant mutants with higher drug resistance rates and low transmission fitness costs have not accounted for influenza (sub)type viruses. Predicting the impacts of neuraminidase inhibitor therapy on infection rates and transmission of drug-resistant viral strains requires further investigation. Objectives: The purpose of this study was to assess the potential risk of oseltamivir-induced resistance for influenza A (H1N1) and A (H3N2) viruses. Materials and methods: An immune-response-based virus dynamic model was used to best fit the oseltamivir-resistant A (H1N1) and A (H3N2) infection data. A probabilistic risk assessment model was developed by incorporating branching process-derived probability distribution of resistance to estimate oseltamivir-induced resistance risk. Results: Mutation rate and sensitive strain number were key determinants in assessing resistance risk. By increasing immune response, antiviral efficacy, and fitness cost, the spread of resistant strains for A (H1N1) and A (H3N2) were greatly decreased. Probability of resistance depends most strongly on the sensitive strain number described by a Poisson model. Risk of oseltamivir-induced resistance increased with increasing the mutation rate for A (H1N1) only. The ≥50% of resistance risk induced by A (H1N1) and A (H3N2) sensitive infected cells were 0.4 (95% CI: 0.28–0.43) and 0.95 (95% CI 0.93–0.99) at a mutation rate of 10−6, respectively. Antiviral drugs must be administrated within 1–1.5 days for A (H1N1) and 2–2.5 days for A (H3N2) virus infections to limit viral production. Conclusion: Probabilistic risk assessment of antiviral drug-induced resistance is crucial in the decision-making process for preventing influenza virus infections.