Hepatitis C virus (HCV) infection and its related liver disease have constituted a heavy burden worldwide. It had been reported that Drinking coffee could decrease mortality risk of HCV infected patients. Caffeic Acid (CA), the Coffee-related organic acid could inhibit HCV replication, however, the detailed mechanism of CA against HCV is unclear. In this study, we showed that CA could notably inhibit HCV replication. Mechanism study demonstrated that CA could induce HO-1 expression, which would trigger the IFNα antiviral response, and the antiviral effect of CA was attenuated when HO-1 activity was inhibited by SnPP (an HO-1 inhibitor). CA could also increase erythroid 2-related factor 2 (Nrf2) expression. When Nrf2 was knocked down by specific siRNA, HO-1 expression was concomitantly decreased while HCV expression was restored. Further study indicated that kelch-like ECH-associated protein 1 (keap1) expression was decreased by CA through p62/Sequestosome1 (p62)-mediated autophagy, which would lead to the stabilization and accumulation of Nrf2. The decrease of keap1 was restored when p62 was silenced by specific p62 siRNA and when autophagy was inhibited, suggesting p62-mediated autophagy was required for CA-mediated keap1 downregulation. Taken together, the results demonstrated that CA could modulate Keap1/Nrf2 interaction via increasing p62 expression, leading to stabilization of Nrf2 and HO-1 induction, and elicit IFNα antiviral response to suppress HCV replication.