Aim  To investigate the changes of serum levels of nuclear factor E2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) in patients with sepsis and their predictive value for the complication of acute kidney injury (AKI) in these patients.  Methods  A total of 132 patients with sepsis treated in our hospital from April 2017 to April 2023 were selected as the study group, and a total of 132 healthy subjects with similar age and sex ratios during the same period were selected as the control group. Serum NRF2 and HO-1 levels were tested in both groups. AKI was evaluated in the study group at the first week after admission. The influencing factors of AKI in sepsis patients were analyzed. The nomogram prediction model of AKI in sepsis patients was constructed and the decision curve analysis (DCA) was performed. Results  Serum NRF2 (2.74±0.54 vs. 1.20±0.21) and HO-1 (6.69±1.27 vs. 3.19±0.52) were higher in the study group than in the control group (t=30.537 and 29.302, P<0.001). The incidence of AKI was 45.45% (60/132) in the 132 sepsis patients within one week after admission. With the increase of serum NRF2 and HO-1, a trend towards the decreased of AKI incidence happened (χ2=35.636 and 28.514, P< 0.001). Multivariate logistic regression showed that NRF2 (OR=0.104, 95% CI: 0.023～0.471) and HO-1 (OR=0.341, 95% CI: 0.168～0.691) were the independent protective factors for AKI in sepsis patients, while SOFA score (OR=1.493, 95% CI: 1.128～1.976), procalcitonin (OR=1.277, 95% CI: 1.070～1.523) and white blood cell count (OR=3.030, 95% CI: 1.550～5.921) were the independent risk factors for AKI in sepsis patients (P<0.05). The nomogram prediction model showed that serum NRF2 and HO-1 had higher predictive values for AKI in sepsis patients, and the consistency indexes were 0.769 and 0.751, respectively. DCA showed that in the threshold range of 0.20～0.78, the net benefit rate of combined assessment of AKI in sepsis patients was better than that of NRF2 or HO-1 alone.  Conclusion  Serum NRF2 and HO-1 levels elevate in sepsis patients, and the combined assay of both levels is helpful to predict the risk of AKI.