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Treatment of hepatitis C virus (HCV) infection has greatly improved in the last 5 years because of the identification of direct-acting antivirals (DAAs). However, concerns exist regarding the emergence of drug resistance-associated substitutions (RASs). In this study, we evaluated the in vivo antiviral effect of three classes of interferons (IFNs), namely, types I, II, and III IFNs, on DAA-resistant HCVs. IFN-α2, IFN-γ, and IFN-λ1 were selected as typical types I, II, and III IFNs, respectively. Human hepatocyte-transplanted chimeric mice were infected with NS3-D168, NS5A-L31-, and NS5A-Y93-mutated HCVs, and the antiviral effect of IFN-α2, IFN-γ, and IFN-λ1 on these HCV RASs was examined. Chimeric mice infected with NS3- and NS5A-mutated HCVs were hydrodynamically injected with IFN-expressing plasmids to evaluate the antiviral effect of IFNs. Serum concentrations of IFNs were maintained for at least 42 days. We found that serum HCV level significantly decreased and serum and hepatic HCV levels reached below detection limit in 5/5 and 3/5 chimeric mice injected with IFN-γ- and IFN-λ1-expressing plasmids, respectively. The antiviral effect of IFN-α2 on DAA-resistant HCVs was weaker than that of IFN-γ and IFN-λ1. Serum ALT levels showed a small and transient increase in mice injected with the IFN-γ-expressing plasmid but not in mice injected with the IFN-λ1-expressing plasmid. However, no apparent histological damage was observed in the liver sections of mice injected with the IFN-γ-expressing plasmid. These results indicate that IFN-γ and IFN-λ1 are an attractive therapeutic option for treating infection caused by NS3- and NS5A-mutated HCV.The in vivo antiviral effect of interferons on direct-acting antivirals-resistant HCVs was evaluated.The antiviral effect of IFN-α2 on direct-acting antivirals-resistant HCVs was poor.IFN-γ and IFN-λ1 exerted antiviral effect on direct-acting antivirals-resistant HCVs.