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Abstract Background Sepsis-associated acute kidney injury (SA-AKI) is common and associated with poor outcomes in critically ill patients. Acetaminophen is often used as an antipyretic and analgesic drug, but the association of acetaminophen use with mortality and recovery of renal function in SA-AKI patients remain unclear. We aimed to investigate the association between acetaminophen use and outcomes in SA-AKI patients. Methods This is a retrospective cohort study based on the MIMIC-IV database. Adult patients with SA-AKI were included in the analysis. The exposure was acetaminophen use within 7 days after the onset of SA-AKI. The primary outcome was 28-day mortality. Secondary outcomes included ICU mortality, in-hospital mortality, 90-day mortality, 1-year mortality, and renal recovery. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% confidence interval (CI) for mortality. Logistic regression models were used to estimate the odd ratio (OR) with 95% CI for renal recovery. Results 6752 patients with SA-AKI were included, and 3892 (57.6%) patients received acetaminophen. Acetaminophen use was associated with decreased 28-day mortality (HR 0.69, 95% CI 0.63–0.75), ICU mortality (HR 0.56, 95% CI 0.50–0.63), in-hospital mortality (HR 0.62, 95% CI 0.57–0.69), 90-day mortality (HR 0.73, 95% CI 0.68–0.79), and 1-year mortality (HR 0.62, 95% CI 0.57–0.69). Acetaminophen use also was associated with improved renal recovery (OR 1.15, 95% CI 1.04–1.28). Conclusions Acetaminophen use is associated with decreased mortality and improved renal recovery in SA-AKI patients.