Objective To assess the efficacy of Dachengqi decoction (DCQD) in preventing post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis (PEP) in high-risk patients. Methods Patients with high-risk factors for PEP who underwent ERCP in our hospital from Dec. 2021 to Jun. 2023 were retrospectively enrolled. According to whether DCQD was administered after ERCP, patients were assigned to DCQD group or control group. General clinical data, endoscopic data, and the occurrence of PEP were recorded and evaluated. Results In total, 60 patients with high-risk factors for PEP were enrolled, including 34 in the DCQD group and 26 in the control group. The baseline data were comparable between the 2 groups. A total of 11 (18.33%) patients developed PEP, including 6 (17.65%) cases in the DCQD group and 5 (19.23%) cases in the control group, and there was no significant difference in the incidence of PEP between the 2 groups (P＞0.05). There were 4 (15.38%) cases of severe acute pancreatitis (SAP) in the control group, while no SAP occurred in the DCQD group, and the incidence of SAP in the DCQD group was significantly lower than that in the control group (P＜0.05). The hospital stay of the DCQD group was (2.59±0.18) d, while the control group was (3.27±0.25) d. The hospital stay in the DCQD group was significantly shorter than that in the control group (P＜0.05). Conclusion The administration of DCQD can reduce the risk of severe PEP and shorten the hospital stay after ERCP in patients with high risk factors for PEP.