Objective To compare the therapeutic efficay of percutaneous transhepatic gallbladder drainage (PTGD) combined with delayed laparoscopic cholecystectomy (LC) versus early LC, and to explore the application strategy of ultrasonic intervention in the perioperative period of difficult cholecystectomy. Methods A total of 78 patients who underwent difficult cholecystectomy in the Affiliated Hospital of Inner Mongolia Medical University from January 2019 to December 2022 were recruited as the study subjects. According to different treatment plans, they were divided into study (n=30, LC surgery in 2-4 weeks after PTGD) and control (n=48, LC immediately after preoperative preparation) groups. Ultrasound was used for bile duct exploration intraoperatively and for treatment of bile leakage postoperatively. The perioperative related indicators were compared between the two groups. SPSS statistics 26.0 was used for statistical analysis. Data comparison between two groups was performed using independent sample t-test, χ² or Fisher test depending on data type. Results The study group had more advanced age [(66.2±13.0) vs (56.5±15.0) years], higher ratio of those ≥60 years old [76.7% (23/30) vs 45.8% (22/48)], and shorter duration of postoperative abdominal drainage [(2.7±0.8) vs (3.4±2.0) d] when compared with the control group (all P<0.05). Open conversion happened in one patient (3.3%) in the study group and four patients (8.3%) in the control group. There were seven patients in both groups having unclear anatomical structures of the Calot triangle, and the surgery was successfully completed after ultrasound exploration for the biliary tract to clarify the anatomical conditions. Only one patient from the study group developed bile leakage on the 2nd day after operation and was discharged after ultrasound-guided puncture and drainage. Conclusion PTGD combined with LC can shorten postoperative abdominal drainage time. The application of ultrasound intervention in the perioperative period of difficult cholecystectomy can significantly reduce surgical difficulty, improve surgical safety, and effectively manage postoperative complications, which is worthy of clinical promotion and application.