Objective To investigate the safety and feasibility of endoscopic cholecystolithotomy after endoscopic ultrasonography (EUS) guided gastric-gallbladder stent implantation in animals. Methods Six miniature pigs of 30-35 kg were selected to laparotomy under intravenous anesthesia. Two to four sterile human stones with a diameter of 0.8-2.0 cm were implanted in their gallbladder. After successful modeling, lumen-apposing metal stent (LAMS) was implanted between the stomach and gallbladder under the guidance EUS. Ultrafine endoscopy was used to search and remove stones after passing the gastric stent into the gallbladder. Endoscopic sphincterotomy (EST) and endoscopic retrogradebiliary drainage (ERBD) was performed to prevent bile leakage. And then ordinary endoscope was used to remove LAMS and close the wound. The success rate, operation time, and incidence of complications were analyzed. Results Five pigs were successfully implanted with LAMS, and the ultrafine endoscope entered the gallbladder smoothly. Small stones were removed from the stone basket, and large stones were completely removed after laser lithotripsy. The total operation time was 87-128 min. No postoperative complications such as bleeding, perforation, infection, and biliary fistula were observed. Failure in 1 pig was due to the first EST plus ERBD, resulting in rapid reduction of gallbladder volume and away from the gastric cavity leading to puncture difficulties. Conclusion EUS-guided LAMS implantation and endoscopic cholecystolithotomy are safe and feasible, and may provide animal experimental evidence for potential therapeutic approach for patients with difficulty in cholecystectomy.