Chili anthracnose is one of the most common and destructive fungal pathogens that affects the yield and quality of pepper. Although WRKY proteins play crucial roles in pepper resistance to a variety of pathogens, the mechanism of their resistance to anthracnose is still unknown. In this study, we found thatCaWRKY50expression was obviously induced byColletotrichum scovilleiinfection and salicylic acid (SA) treatments.CaWRKY50-silencing enhanced pepper resistance toC. scovillei, while transient overexpression ofCaWRKY50in pepper increased susceptibility toC. scovillei. We further found that overexpression ofCaWRKY50in tomatoes significantly decreased resistance toC. scovilleiby SA and reactive oxygen species (ROS) signaling pathways. Moreover, CaWRKY50 suppressed the expression of two SA-related genes,CaEDS1(enhanced disease susceptibility 1) andCaSAMT1(salicylate carboxymethyltransferase 1), by directly binding to the W-box motif in their promoters. Additionally, we demonstrated that CaWRKY50 interacts with CaWRKY42 and CaMIEL1 in the nucleus. Thus, our findings revealed that CaWRKY50 plays a negative role in pepper resistance toC. scovilleithrough the SA-mediated signaling pathway and the antioxidant defense system. These results provide a theoretical foundation for molecular breeding of pepper varieties resistant to anthracnose.