Background: The role of oral antibiotic prophylaxis (OAP) and mechanical bowel preparation (MBP) in the prevention of surgical site infection (SSI) after colorectal surgery is still controversial. The aim of this study was to analyze the effect of a bundle including both measures in a National Infection Surveillance Network in Catalonia. Methods: Pragmatic cohort study to assess the effect of OAP and MBP in reducing SSI rate in 65 hospitals, comparing baseline phase (BP: 2007-2015) with implementation phase (IP: 2016-2019). To compare the results, a logistic regression model was established. Results: Out of 34,421 colorectal operations, 5180 had SSIs (15.05%). Overall SSI rate decreased from 18.81% to 11.10% in BP and IP, respectively (OR 0.539, CI95 0.507-0.573, p < 0.0001). Information about bundle implementation was complete in 61.7% of cases. In a univariate analysis, OAP and MBP were independent factors in decreasing overall SSI, with OR 0.555, CI95 0.483-0.638, and OR 0.686, CI95 0.589-0.798, respectively; and similarly, organ/space SSI (O/S-SSI) (OR 0.592, CI95 0.494-0.710, and OR 0.771, CI95 0.630-0.944, respectively). However, only OAP retained its protective effect at both levels at multivariate analyses. Conclusions: oral antibiotic prophylaxis decreased the rates of SSI and O/S-SSI in a large series of elective colorectal surgery.