Chronic hepatitis C virus (HCV) infection increases the risk of liver cirrhosis and hepatocellular carcinoma. In the last decade, the current standard HCV treatment, pegylated interferon and ribavirin, have limited efficacy and significant side effects. Novel direct acting antivirals show promise, but escape mutants are expected, along with potential side effects. Pycnogenol®, a French maritime pine extract, has been reported to have antioxidant and antiviral effects. Here, we evaluated the effect of Pycnogenol® on HCV replication. Wild-type and protease inhibitor (VX-950; telaprevir)-resistant HCV replicon cells were treated with Pycnogenol®, Pycnogenol® and interferon-alpha, and ribavirin and telaprevir. Pycnogenol® effects on replication were also evaluated in HCV-infected chimeric mice. Pycnogenol® treatment showed antiviral effects without cytotoxicity at doses up to 50 μg/mL. Pycnogenol® in combination with interferon-alpha or ribavirin showed synergistic effects. Moreover, Pycnogenol® inhibited HCV replication in telaprevir-resistant replicon cells; telaprevir and Pycnogenol® acted additively to reduce HCV RNA levels in wild-type HCV replicon cells without significantly increasing cytotoxicity. Pycnogenol® antiviral activity was higher than its components procyanidin and taxifolin. Further, treatment of infected chimeric mice with Pycnogenol® suppressed HCV replication and showed a synergistic effect with interferon-alpha. In addition, Pycnogenol® treatment resulted in dose-dependent reduction of reactive oxygen species in HCV replicon cell lines. Pycnogenol® is a natural product that may be used to improve the efficacy of the current standard antiviral agents and even to eliminate resistant HCV mutants.