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Cisplatin plays a pivotal role in the chemotherapy treatment of various cancers, but its use is often limited due to its nephrotoxic side effects. Identifying compounds that can mitigate cisplatin-induced nephrotoxicity is therefore of great importance. This study focused on evaluating the protective effects of reserpine against cisplatin-induced acute kidney injury. Reserpine was found to significantly safeguard against kidney damage caused by cisplatin, as indicated by the decreased levels of serum creatinine, blood urea nitrogen, and lactate dehydrogenase induced by cisplatin. Moreover, reserpine improved kidney histology damage caused by cisplatin treatment, with hematoxylin-eosin and periodic acid-Schiff staining revealing notable recovery from renal injury. Mechanistically, reserpine mitigated oxidative stress triggered by cisplatin and exhibits the ability to inhibit ferroptosis both in vivo and in vitro. Additionally, reserpine blocked the activation of the cGAS/STING signaling pathway and the subsequent expression of inflammatory genes, thus reducing inflammation-driven kidney damage. In summary, the findings suggest that reserpine offers a promising new strategy for preventing nephrotoxicity induced by cisplatin.