Background: Proton pump inhibitors (PPIs) are effective in reducing marginal ulcers after pancreatoduodenectomy. However, their impact on perioperative complications has not been defined. Methods: We retrospectively analyzed the effect of postoperative PPIs on 90-day perioperative outcomes in all patients who underwent pancreatoduodenectomy at our institution from April 2017 to December 2020. Results: 284 patients were included; 206 (72.5%) received perioperative PPIs, 78 (27.5%) did not. The two cohorts were similar in demographics and operative variables. Postoperatively, the PPI cohort had significantly higher rates of overall complications (74.3% vs. 53.8%) and delayed gastric emptying (28.6% vs. 11.5%), p < 0.05. However, no differences in infectious complications, postoperative pancreatic fistula, or anastomotic leaks were seen. On multivariate analysis, PPI was independently associated with a higher risk of overall complications (OR 2.46, CI 1.33–4.54) and delayed gastric emptying (OR 2.73, CI 1.26–5.91), p = 0.011. Four patients developed marginal ulcers within 90-days postoperatively; all were in the group who received PPIs. Conclusion: Postoperative proton pump inhibitor use was associated with a significantly higher rate of overall complications and delayed gastric emptying after pancreatoduodenectomy.