Background: Enhanced recovery after surgery (ERAS) offers lower overall morbidity rates and shorter hospital stay after colorectal surgery (CRS); high adherence rates to ERAS may significantly reduce major morbidity (MM), anastomotic leakage (AL), and mortality (M) rates as well. Methods: Prospective enrollment of patients submitted to elective CRS with anastomosis in two separate 18- and 12-month periods among 78 surgical centers in Italy from 2019 to 2021. Adherence to ERAS pathway items was measured upon explicit criteria in every case. After univariate analysis, independent predictors of primary endpoints (MM, AL, and M rates) were identified through logistic regression analyses, presenting odds ratios (OR) and 95% confidence intervals. Results: An institutional ERAS status was declared by 48 out of 78 (61.5%) participating centers. The median overall adherence to ERAS was 75%. Among 8,359 patients included in both studies, MM, AL, and M rates were 6.3%, 4.4%, and 1.0%, respectively. Several patient-related and treatment-related variables showed independently higher rates for primary endpoints: male gender, American Society of Anesthesiologists class III, neoadjuvant treatment, perioperative steroids, intra- and/or postoperative blood transfusions, length of the operation >180’, surgery for malignancy. On the other hand, ERAS adherence >85% independently reduced MM (OR, 0.91) and M (OR, 0.25) rates, whereas no mechanical bowel preparation independently reduced AL (OR, 0.68) rates. Conclusions: Among other patient- or treatment-related variables, ERAS adherence >85% independently reduced MM and M rates, whereas no mechanical bowel preparation independently reduced AL rates after CRS.