<p>Cisplatin remains a cornerstone chemotherapeutic agent for a broad spectrum of solid malignancies; however, the emergence of intrinsic and acquired resistance severely limits its clinical efficacy. Central to the cellular decision between DNA damage repair and apoptosis following cisplatin exposure is the tumor suppressor p53, whose function is tightly governed by its primary negative regulator, Murine Double Minute 2 (MDM2). This review provides a critical synthesis of the molecular interplay within the MDM2/p53 axis and its direct impact on cisplatin sensitivity. We discussed how deregulation of this axis via TP53 mutational inactivation or MDM2 overexpression enables tumor cells to tolerate cisplatin-induced genotoxic stress. Specifically, we analyzed the dual role of MDM2: its E3 ubiquitin ligase activity that targets p53 for proteasomal degradation, and its emerging p53-independent functions in promoting DNA repair fidelity. Furthermore, we evaluated the therapeutic implications of targeting this pathway with small-molecule MDM2 antagonists. We assessed preclinical and clinical evidence supporting the use of MDM2 inhibition to lower the apoptotic threshold and re-sensitize resistant tumors to cisplatin. Therefore, an understanding of the MDM2/p53 feedback loop is essential for optimizing cisplatin-based regimens and developing rational combination therapies to circumvent chemoresistance.</p>