Open liver resection necessitates a substantial upper abdominal inverted-L incision, resulting in severe pain and compromising patient recovery. Despite the efficacy of epidural analgesia in providing adequate postoperative analgesia, the potential epidural-related adverse effects should be carefully considered. This study aims to compare the efficacy and safety of continuous epidural analgesia and intravenous analgesia in open liver resection. A retrospective study was conducted, collecting data from patients who underwent open liver resection between 2007 and 2017. Propensity score matching was implemented to mitigate confounding variables, with patients being matched in a 1:1 ratio based on propensity scores. The primary outcome was the comparison of postoperative morphine consumption at 24, 48, and 72hours between the two groups. Secondary outcomes included pain scores, postoperative outcomes, and epidural-related adverse effects. A total of 612 patients were included, and after matching, there were 204 patients in each group. Opioid consumption at 24, 48, and 72hours postoperatively was statistically lower in the epidural analgesia group compared to the intravenous analgesia group (p < 0.001). However, there was no significant difference in pain scores (p = 0.422). Additionally, perioperative hypotension requiring treatment, as well as nausea and vomiting, were significantly higher in the epidural analgesia group compared to the intravenous analgesia group (p < 0.001). Epidural analgesia is superior to intravenous morphine in terms of reducing postoperative opioid consumption within the initial 72h after open liver resection. Nevertheless, perioperative hypotension, which necessitates management, should be approached with consideration and vigilance. The study was registered in the Clinical Trials Registry at www. gov/ , NCT number: NCT06301932.