Objective <p>The aim of this study is to assess the predictive value of serum proenkephalin A 119–159 (penKid) levels for acute kidney injury (AKI) associated with sepsis (SA-AKI).</p> Methods <p>A retrospective cohort study was conducted from September 2021 to September 2022. Clinical characteristics and laboratory parameters were compared between the AKI and non-AKI groups. Risk factors for the development of SA-AKI were identified using Cox regression analysis. In addition, receiver operating characteristic (ROC) curve analysis was conducted to assess the predictive ability of each identified risk factor for AKI among patients with sepsis.</p> Results <p>A total of 161 patients diagnosed with sepsis or septic shock were included, among whom 66 developed AKI, representing an incidence rate of 41.0%. Baseline lactic acid (LA) levels were significantly higher in the AKI group compared to the non-AKI group. Similarly, baseline penKid concentrations were significantly elevated in the AKI group compared to the non-AKI group. Serum LA and penKid levels were identified as independent risk factors for AKI in patients with sepsis or septic shock. ROC curve analysis demonstrated that the baseline penKid concentration significantly predicted AKI in this population (<i>p</i> &lt; 0.001), with an area under the curve of 0.867, sensitivity of 0.788, and specificity of 0.832 when the penKid threshold was set at 2.41&#xa0;μg/L.</p> Conclusion <p>Serum penKid levels may serve as a reliable biomarker for the early detection of AKI in patients presenting with sepsis or septic shock.</p>