Objective We compared the effect of three anesthetic procedures on the establishment of and recovery effect on the young minipig models of skull defect, and explore an optimal anesthetic procedure for long-lasting surgical experiment in minipigs. Methods Thirty 3-month old Guizhou minipigs (male:female=1:1) were randomly divided into three groups, 10 in each group. The group A was given with midazolam and ketamine i.p., the group B received lumianning II i.p., and the group C received midazolam combined with ketamine and lumianning II i.p. The induction time of anesthesia, the first anesthesia maintenance time, the first anesthesia maintenance period after additional use of anesthetics, the second time anesthesia maintenance period after additional use of anesthetics, the recovery period, the number of times of additional intraoperative use of anesthetics, cumulative amount of anesthetics used, and the adverse reaction and mortality rates of the animals after anesthesia were observed and analyzed. Results The anesthesia induction time in the group B was significantly longer than that in the groups A and C (P<0.05 for both). The anesthesia maintenance time and the anesthesia maintenance after first and second additional use of anesthetics in the groups A were significantly longer than those of the groups A and B (P<0.05 for both). The recovery periods in groups A and C were shorter than that of the group B (P<0.05 for both). The number of times of additional intraoperative use of anesthetics, the total dose of anesthetics, the adverse reaction and mortality rates in the group C were significantly lower than those of the groups A and B (P<0.05 for both). Conclusions The combination of midazolam with ketamine and lumianning II is a simple, easy to control the anesthesia depth, and a safe method to anesthetize young minipigs in long-lasting surgical experiment.