Objective To investigate the clinical applications of goal-directed fluid therapy for pancreatoduodenectomy. Methods A total of 40 patients undergoing pancreatoduodenectomy under general anesthesia were randomly divided into two groups, G and C, with 20 cases in each group. Goal-directed fluid therapy was used in Group G, whereas conventional fluid therapy was used in group C. The intraoperative hemodynamics, liquid management, duration of the first postoperative gastrointestinal ventilation, postoperative renal function, serum lactate, and the incidence of postoperative complications were recorded. Results Compared with group C, the CI increased and SVV decreased (P ＜ 0.05) at T3 to T5, and MAP increased at T4 to T5 (P ＜ 0.05). The amount of fluid infusion and total infusion in group G were less than that of group C (P ＜ 0.05), and the number of vasoactive drugs was greater than that of group C (P ＜ 0.05). The duration of the first postoperative gastrointestinal ventilation in group G was shorter than that of group C (P ＜ 0.05). There were no significant differences between the 2 groups for the incidence of serum lactate, BUN, Cr, and the incidence of postoperative complications (P＞ 0.05).Conclusion For major complex operations, such as pancreaticoduodenectomy, goal-directed fluid therapy can guide intraoperative fluid therapy more accurately with individual optimizations, and has more advantages in maintaining intraoperative hemodynamics stability and improving postoperative outcome.