<p>Muscle wasting is a common event among cancer patients receiving chemotherapy treatment and has been reported to affect their survival. However, current therapies for counteracting this side effect are ineffective. This study investigates quercetin’s efficacy against cisplatin-induced muscle atrophy and its mechanism. Using both C2C12 myotube and mouse models, we found quercetin pretreatment significantly alleviates cisplatin-induced muscle wasting. Mechanistically, transcriptome analysis identified that the Hippo signaling pathway was involved in cisplatin-induced muscle atrophy. Quercetin restored the activity of this pathway, including the expression and nuclear localization of its effector YAP1. Furthermore, quercetin mitigated cisplatin-induced muscle damage by improving mitochondrial membrane quality and function. Molecular docking revealed a direct interaction between quercetin and YAP1. Additionally, the possible interaction between YAP1 and mitochondrial function was revealed. Our findings demonstrate that quercetin attenuates cisplatin-induced muscle atrophy by modulating the Hippo/YAP1 pathway and preserving mitochondrial homeostasis, highlighting its therapeutic potential.</p> Graphical abstract <p></p>