Cisplatin is a cornerstone chemotherapeutic agent used widely to treat various solid malignancies. Despite its efficacy, the usage of cisplatin is limited by its dose-dependent nephrotoxicity causing cisplatin-induced acute kidney injury (AKI) in up to 45% of treated patients. Current preventive strategies are limited to supportive measurement resulting in questionable clinical outcomes. N-acetylcysteine (NAC), a thiol-containing compound with antioxidant and anti-inflammatory properties, is already known for its safety.. This review aims to explore the mechanisms of cisplatin-induced AKI, the role of NAC in its prevention, and the current evidence.. A narrative review has been conducted of several literature, including preclinical and clinical studies evaluating NAC’s efficacy in preventing cisplatin-induced AKI.. Cisplatin has cytotoxic effect via DNA structures disruption, leading to impairment of cell repair mechanism, triggering apoptosis that works effectively against cancer cells. However, cisplatin also accumulates in renal proximal tubular epithelial cells, disrupting DNA structures, increasing reactive oxygen species (ROS), inducing mitochondrial dysfunction and inflammation, all leading to apoptosis. NAC can counteract these mechanisms by scavenging ROS directly via its thiol group and indirectly by replenishing glutathione. Preclinical studies have demonstrated consistent NAC nephroprotective effects. However, findings from clinical studies remain inconsistent due to limited sample sizes, varied dosing regimens, and differences in administration routes, making comparison between studies difficult to conduct.. NAC exhibits strong nephroprotective properties through antioxidant, anti-inflammatory, and cytoprotective mechanisms as consistently shown in preclinical studies. Despite the limited current clinical evidence supporting these findings, NAC remains a promising agent for cisplatin-induced AKI prevention. Future research should focus on large-scale, well-designed, standardized clinical trials with optimized dosing strategies to validate NAC’s efficacy and establish its clinical role.