Microbes have developed their own specific strategies to cope with reactive oxygen species (ROS). Catalase, a heme‐containing tetramer expressed in a broad range of aerobic fungi, shows remarkable efficiency in degrading hydrogen peroxide (H2O2) for fungal survival and host invasion. Here, it is demonstrated that catalase inactivation by blue light renders fungal cells highly susceptible to ROS attack. To confirm catalase as a major molecular target of blue light, wild type Candida albicans are systematically compared with a catalase‐deficient mutant strain regarding their susceptibility to ROS through 410 nm treatment. Upon testing a wide range of fungal species, it is found that intracellular catalase can be effectively and universally inactivated by 410 nm blue light. It is also found that photoinactivation of catalase in combination with ROS‐generating agents is highly effective in total eradication of various fungal species, including multiple Candida auris strains, the causative agent of the global fungal epidemic. In addition, photoinactivation of catalase is shown to facilitate macrophage killing of intracellular Candida albicans. The antifungal efficacy of catalase photoinactivation is further validated using a C. albicans‐induced mouse model of skin abrasion. Taken together, the findings offer a novel catalase‐photoinactivation approach to address multidrug‐resistant Candida infections. Most of the fungal microbes have evolved to scavenge H2O2 through expression of catalase. Here, it is found that catalase from most of pathogenic fungi (Candida auris included) can be inactivated by blue light, especially at 410 nm. Photoinactivation of catalase sensitizes these fungal cells highly susceptible to H2O2‐producing agents and immune cells.