IMPORTANCE: Antimicrobial stewardship (AMS) programs optimize antibiotic use and mitigate antimicrobial resistance. The literature on the efficacy of AMS programs in pancreatic surgery is limited. OBJECTIVE: To investigate the association of a multifaceted AMS intervention targeting surgical antibiotic prophylaxis (SAP) with the rate of surgical site infections (SSIs) following pancreatic surgery. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was a multicenter, before-and-after analysis conducted at 3 Italian centers. The intervention cohort included adult patients aged 18 years or older who underwent pancreatectomy between January 1, 2020, and December 31, 2022, while the historical cohort included patients from January 1, 2015, to December 31, 2019. EXPOSURE: A multiprofessional, multidimensional ASM program that included a bundle of interventions and pivoted on preoperative rectal screening for multidrug-resistant bacteria and targeted SAP. MAIN OUTCOMES AND MEASURES: The primary outcomes were SSI incidence and SAP appropriateness, assessed through the coverage rate of rectal and biliary isolates. Data were analyzed using propensity score weighting. Secondary outcomes evaluated were other postoperative outcomes (eg, pancreatic fistula rate, length of stay), antibiotic use, and costs. RESULTS: A total of 3387 patients (median [IQR] age, 66 [66-73] years; 1788 male [52.8%]) were included, with 1219 in the intervention cohort and 2168 in the historical cohort. After implementing the AMS program, a statistically significant reduction was found in rates of overall (30.1% vs 20.6%), superficial (5.8% vs 2.5%), deep (0.9% vs 0.3%), and organ-space (26.3% vs 19.3%) SSIs. After propensity score weighting, the odds ratios for the estimated mean treatment effect were 0.92 (95% CI, 0.89-0.96) for overall, 0.85 (95% CI, 0.78-0.93) for superficial, and 0.95 (95% CI, 0.92-0.99) for organ-space SSIs. Surgical antibiotic prophylaxis coverage increased significantly for rectal screening (87.2% vs 100%) and biliary bacterial colonization (59.7% vs 68.7%). Complications, infections, length of stay, and antibiotic consumption also decreased, with an overall cost savings of 247 460 euros. CONCLUSIONS AND RELEVANCE: These findings suggest that a multifaceted, pancreatic surgery-specific AMS program is associated with decreased rates of SSIs, increased coverage of isolated bacteria, improved clinical outcomes, more judicious antibiotic use, and lower costs.