To assess the role of protein-energy malnutrition on perioperative outcomes in patients with pancreatic cancer undergoing open pancreaticoduodenectomy. We conducted a retrospective observational cohort study and investigated patients ≥ 18 years old with pancreatic cancer undergoing open pancreaticoduodenectomy within the National inpatient sample database during 2012–2014. The study population was divided into two groups based on the presence of protein-energy malnutrition. In-hospital mortality, length of stay, cost of hospitalization, and in-hospital complications were compared between the two groups. Logistic and linear regression analyses were used to adjust for potential confounders. A trend analysis was further conducted on the in-hospital outcomes. Of the 12,785 patients aged ≥ 18 years undergoing open pancreaticoduodenectomy during years 2012–2014, 9865 (77.0%) had no protein-energy malnutrition and 2920 (23.0%) had protein-energy malnutrition. Patients with protein-energy malnutrition were found to have significantly higher mortality rate, longer length of hospital stay, and higher total hospital cost compared to those without protein-energy malnutrition. The risks of gastroparesis, small bowel obstruction, intraoperative and postoperative hemorrhage, infectious complications, and several systemic complications were found to be significantly higher in the protein-energy malnutrition group in a multivariate regression model. A study of trends from 2009 to 2012 revealed an increasing prevalence of protein-energy malnutrition, a declining trend in mortality and length of stay and a stable total hospital cost in the protein-energy malnutrition group. Protein-energy malnutrition was found to be associated with higher mortality, longer length of hospital stay and greater hospital cost in pancreatic cancer patients undergoing open pancreaticoduodenectomy, as well as increased occurrence of various systemic complications. Attention should be paid to patients’ nutritional status, which can be corrected before surgery as an effective means to optimize postoperative results.