Background <p>Acute kidney injury (AKI) remains a frequent complication in intensive care unit (ICU) settings. Clopidogrel, a P2Y12 receptor inhibitor, has been reported to possess anti-inflammatory, antioxidant, immunomodulatory, and anti-apoptotic effects. However, evidence regarding its survival benefit in critically ill patients with AKI remains limited. This study aims to evaluate the association between clopidogrel use and mortality in critically ill patients with AKI.</p> Methods <p>Using MIMIC-IV database, we conducted a retrospective cohort study including 28,457 AKI patients, of whom 3344 were clopidogrel users. The exposure was defined as clopidogrel use during the ICU stay. The primary and secondary outcomes were 30-day mortality and in-hospital mortality, respectively. Multivariable Cox proportional hazards models were used to assess the risk of death. In order to verify the robustness of the results, we employed various techniques such as inverse probability weighting (IPTW), pairwise algorithms (PA), overlap weights (OW), and standardized mortality ratio weighting (SMRW).</p> Results <p>After PSM (<i>n</i> = 6668), clopidogrel users showed a lower 30-day mortality (10.1% vs. 12.0%, <i>p</i> = 0.012), with an adjusted HR of 0.83 (95%CI 0.72–0.96, <i>p</i> = 0.011). Kaplan-Meier analysis was consistent with these findings, demonstrating a significantly higher survival probability in clopidogrel users during the period of hospitalization in the ICU and at 30 days (Log-rank <i>p</i> = 0.0017). After adjustment for potential confounders using PSM and propensity score, plus the use of IPTW, SMRW, PA, and OW, our results remained consistent across different methods, with hazard ratios ranging from 0.73 to 0.80, all <i>p</i> values &lt; 0.001.</p> Conclusion <p>Clopidogrel use was associated with decreased mortality among critically ill patients with AKI. </p>