Background <p>Major surgeries like pancreatoduodenectomy carry high risks for perioperative complications, especially in older patients and those with comorbidities. While perioperative care has improved, the role of prehabilitation—defined as structured preoperative physical and nutritional preparation—remains underexplored in pancreatic surgery. This study evaluated the impact of a multimodal prehabilitation program on postoperative outcomes in patients undergoing pancreatoduodenectomy.</p> Methods <p>A retrospective single-center matched-pair analysis was conducted including patients who underwent elective pancreatoduodenectomy after implementation of a structured prehabilitation program (January 2023-October 2024) and a historical control group. Matching criteria were sex, ASA class, and type of procedure. The multimodal home-based prehabilitation program comprised physical exercise, breathing training, and individualized nutritional support. Primary outcomes were postoperative complications, length of hospital stay, and recovery parameters. Multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW) analyses were performed to adjust for confounding.</p> Results <p>Of 116 eligible patients, 36 completed prehabilitation and were matched to 36 controls. Overall postoperative complications were lower after prehabilitation (44.4% vs. 66.7%, <i>p</i> = 0.053), while severe complications (Clavien-Dindo 3–4) were significantly reduced (16.7% vs. 38.9%, <i>p</i> = 0.042). Postoperative blood transfusion rates were lower (5.6% vs. 22.2%, <i>p</i> = 0.041), and hospital stay was shorter (13 vs. 16&#xa0;days, <i>p</i> = 0.017). IPTW-adjusted analyses confirmed a consistent reduction in postoperative complications (OR 0.425), although statistical significance was not consistently reached. Subgroup analysis of patients ≥ 80&#xa0;years demonstrated a significant reduction in complications (25% vs. 100%, <i>p</i> = 0.028).</p> Conclusions <p>Prehabilitation is feasible and associated with improved postoperative outcomes after pancreatoduodenectomy, particularly regarding severe complications and length of hospital stay. Although limited by sample size and adherence, the findings suggest that prehabilitation may enhance recovery, especially in elderly patients. Larger prospective studies are warranted to confirm these results.</p> Trial registration <p>The study was registered on June 18, 2025 in the German Clinical Trials Register (DRKS) under the identification number DRKS00037231.</p>