Abstract Background and Aims Post-operative acute kidney injury (PO-AKI) is a common complication of colorectal cancer (CRC) surgery associated with increased morbidity and mortality, and higher hospital costs. Specific treatment of AKI is still limited, supporting the importance of preventing AKI. Identification of patients at high risk may allow early interventions, including closer monitoring and perioperative optimization. This study aimed to identify predictors of PO-AKI by assessing the association between preoperative factors and the occurrence of PO-AKI. Method We conducted a nationwide cohort study including adult CRC surgery patients in 2010–2021 using Danish health registries. We defined PO-AKI as AKI within 7 days after the CRC surgery according to the 2012 KDIGO criteria using creatinine measurements. A list of patient characteristics associated with AKI was identified using existing literature. We obtained information on variables using population-based health registries containing data on diagnosis codes, redeemed prescriptions, and laboratory data. We investigated the individual predictive factors by estimating PO-AKI risks and the odds ratios (ORs) with 95% confidence intervals (CIs) adjusting for sex and age. Results We identified 35,650 CRC surgery patients, of whom 24,555 had creatinine measurements during the study period, making them eligible for further analysis. Among these patients, we identified 2,694 cases of PO-AKI, corresponding to a 11% risk of PO-AKI. The risk of PO-AKI was higher for males (13.5% vs. 8.4%, aOR=1.76 [1.62-1.91]), and patients with diabetes (15.4% vs. 10.2%, aOR=1.46 [1.32-1.61]), cardiovascular disease (15.4% vs. 9.9%, aOR=1.38 [1.26-1.52]), CKD (18.9% vs. 9.2%, aOR=1.99 [1.80-2.19]), COPD (16.6% vs. 10.3%, aOR=1.59 [1.42-1.78]), and hypertension (13.6% vs. 7.5%, aOR=1.68 [1.53-1.84]). When examining potentially nephrotoxic medicine, the risk was higher in ACE-I/ARB users (14.5% vs. 9.6%, aOR=1.44 [1.32-1.56]) and similar in NSAID users and nonusers (10.3% vs. 11.0%, aOR=1.00 [0.84-1.19]). Conclusion We found that male gender, diabetes, cardiovascular disease, CKD, COPD, hypertension, and the use of ACE-I/ARB medications were associated with a higher risk of PO-AKI. Interestingly, users and nonusers of NSAIDs had similar risks of AKI. The identification of high-risk groups, such as those with pre-existing comorbidities or users of specific medications, may aid clinicians in identifying patients with a particularly high risk of PO-AKI.