Objective To compare the operation difficulty, surgical effect, postoperative complications and the influence of bile on gastric mucosa of endoscopic ultrasonography-guided gallbladder drainage (EUS-GBD) through the gastric antrum and the duodenal bulb. Methods Eight pigs were divided into two groups, and 4 pigs in each group underwent EUS-GBD through the gastric antrum and the duodenal bulb under laparoscopy. The animals were sacrificed 10 days after successful modeling, and the anastomosis and gastric mucosa were observed for histological changes. Results Three pigs in each group were completely successful. The success rate of the two groups was 75%. The average operation time of the gastric antrum group (21.67 min) was shorter than that of the duodenum group (26.67min) (P < 0.05), but the total pathological score of gastric mucosal injury (8.33 points) was higher than that of the duodenal bulb group (6.33 points) (P < 0.05). Conclusions In the animal model of pigs, the endoscopic ultrasonography-guided gallbladder drainage through duodenal bulb is slightly more difficult and has less postoperative complications than through gastric antrum .