Abstract Background Post-hepatectomy liver failure (PHLF) is a serious complication of hepatectomy. The current criteria for PHLF diagnosis (ISGLS consensus) require laboratory data on or after postoperative day (POD) 5, which may delay treatment for patients at risk. The present study aimed to determine the associations between early postoperative (POD1) serum aminotransferase levels and PHLF. Methods The medical records of patients who underwent hepatectomy at Ramathibodi Hospital from January 2008 to December 2019 were retrospectively examined. Patients were classified into PHLF and non-PHLF groups. Preoperative characteristics, intraoperative findings, and early postoperative laboratory data (serum AST, ALT, bilirubin, and international normalized ratio (INR) on POD0 to POD5) were analyzed. Results A total of 890 patients were included, of whom 31 (3.4%) had PHLF. Cut-off points for AST of 260 U/L and ALT of 270 U/L on POD1 were predictive of PHLF. In multivariate analysis, AST >260 U/L on POD1, ICG-R15, major hepatectomy, blood loss, and INR were independently associated with PHLF. Conclusions Early warning from elevated serum AST on POD1, before a definitive diagnosis of PHLF is made on POD5, can help alert physicians that a patient is at risk, meaning that active management and vigilant monitoring can be initiated as soon as possible.