Candida albicans is the most leading cause of life-threatening fungal invasive infections, especially for vulvovaginal candidiasis (VVC). Resistance and tolerance to common fungicide has risen great demands on alternative strategies for treating C. albicans infections. In the present study, ferroptosis has been proven to occur in C. albicans by directly exposed to FeSO via induing hallmarks of ferroptosis, including Fe overload burden, ROS eruption and lipid peroxidation. Transcriptomic profile gave the great hints of the possible mechanism for fungal ferroptosis that FeSO disturb pathways associated to ribosome, tyrosine metabolism, triglyceride metabolism and thiamine metabolism, thus mobilizing death-related gene synthesis. Inspired by the results, a FeSO-loaded hydrogel was prepared as an antifungal agent to treat C. albicans infection. This hydrogel exhibited excellent dressing properties and maintained superior antifungal activity by characterization tests. Besides, mice treated by this composite hydrogel displayed excellent therapeutic efficacy. These results highlighted the potential therapeutic use of FeSO as an innovative strategy in treating C. albicans infections by targeting ferroptosis.