Vaginal candidiasis caused byCandida albicans is a chronic, recurrent disease that is difficult to treat. Current available antifungal drugs have limited efficacy and cause adverse effects necessitating novel therapeutic options. In this study, a novel metal-organic framework (MOF) containing the sonosensitizer rose bengal (RB) and decorated with silver nanoparticles (AgNPs), Fe-MOF(RB)@AgNPs (MRA), is developed which integrates chemodynamic therapy (CDT) and sonodynamic therapy (SDT) with the long-term antifungal effects of AgNPs into a single nanoscale entity. MRA exhibited low cytotoxicity in mammalian cells and strong catalytic activity for the conversion of H 2 O 2 to •OH under acidic conditions, similar to those found in vaginal candidiasis. When exposed to ultrasound, MRA generated 1 O 2 and offered rapid synergistic fungicidal effects through CDT and SDT, as well as long-lasting antifungal benefits through AgNPs, leading to the complete eradication of drug-resistant C. albicans. Moreover, MRA exhibited 99.999% efficacy against a clinical isolate of drug-resistant C. albicans at 120 µg mL −1 . Hence, MRA has considerable potential for clinical applications in the treatment of drug-resistant C. albicans-induced vaginal candidiasis.