Objective To explore the efficacy of 4 minimally invasive surgery for the treatment of cholecystolithiasis with choledocholithiasis. Methods A total of 144 patients who was diagnosed as cholecystolithiasis with choledocholithiasis in our hospital from Jan. 2017 to Jun. 2018 were selected, and randomly divided into laparoscopic cholecystectomy (LC)+laparoscopic common bile duct exploration (LCBDE) with T tube drainage group (n=44), LC+LCBDE with primary suture group (n=35), LC+laparoscopic transcystic common bile duct exploration (LTCBDE) group (n=27), and LC+endoscopic retrograde cholangiopancreatography (ERCP)/endoscopic sphincterotomy (EST) group (n=38). The surgical conditions, postoperative indexes, and early and long-term complications of the 4 groups were compared and analyzed. Results There were no significant diffierences in operation success rate, operation time, intraoperative bleeding or anal exhaust time among the 4 groups (all P>0.05). The proportion of postoperative discomfort (such as bloating and vomitting) in the LC+LCBDE with T tube drainage group was significantly higher, the score of gastrointestinal quality of life index was significantly lower, the postoperative hospital stay in the LC+LTCBDE group was significantly shorter, and the postoperative serum amylase level in the LC+ERCP/EST group was significantly higher than the other 3 groups (all P<0.05). There were no serious postoperative complications in the 4 groups. In the LC+LCBDE with T tube drainage group, 2 cases had biliary tract infection, 1 had T tube detachment, and 4 had hyperamylasemia; in the LC+LCBDE with primary suture group, 4 cases had biliary leakage and 2 had hyperamylasemia; in the LC+LTCBDE group, 2 cases had hyperamylasemia; and in the LC+ERCP/EST group, 8 cases had hyperamylasemia and 2 had pancreatitis during the early postoperative period. After follow-up for more than half a year, there were 1 case of stone residue, 1 case of stone recurrence and 1 case of biliary stenosis in the LC+LCBDE with T tube drainage group; and 4 cases of stone recurrence and 2 cases of biliary stenosis in the LC+ERCP/EST group. Conclusion The 4 minimally invasive surgery methods are all effective for the treatment of cholecystolithiasis with choledocholithiasis. The LTCBDE has the advantages of minimal trauma, rapid recovery and low complication incidence, and it is worthy of clinical promotion. The surgeon should choose the best surgery according to the individual condition and surgical indications of the patients.