Nutrition support is essential for surgical patients. Patients undergoing pancreaticoduodenectomy (PD) require tremendous nutrient support but also faced with risks of infection and gastrointestinal complications. Early parenteral nutrition has recently shown benefits while limited information provided about the influence on metabolism. This prospective single-center cohort study used plasma metabolomics to clarify metabolic alteration after early parenteral nutrition followed with enteral nutrition. Patients undergoing pancreaticoduodenectomy (n = 52) were enrolled. 36 patients received parenteral nutrition within 3 days postoperatively followed with EN (TPN group), 16 patients received standard fluids followed with EN (GIK group). We found that the weight loss is reduced in TPN group while the other clinical outcomes and inflammatory cytokines showed no statistical significance. The TPN group showed significance in amino acids, lipid, and phospholipids metabolism compared with the GIK group. Moreover, integration analysis indicated that early TPN could promote the metabolism of long-chain fatty acids, phospholipids, ketone bodies, and branched-chain amino acids. We conclude that early TPN support followed with EN for patients undergoing PD reduced the perioperative weight loss and promoted the metabolic transition to anabolic metabolism with the recovery of lipid metabolism, suggesting its benefits for the recovery of patients.