Objective: The role of selective decontamination with oral antibiotics (OABs) and mechanical bowel preparation (MBP) prior to elective colorectal surgery is still widely debated. The objective of this study was to compare the outcomes of selective decontamination with neomycin, metronidazole and MBP compared to those of decontamination with MBP alone or with no preparation. Methods: Selective decontamination with neomycin and metronidazole combined with bowel preparation was introduced prior to elective colorectal surgery as part of an enhanced recovery after surgery program at Westmead Hospital, a major Australian tertiary referral hospital, between June 2017 and January 2023. Comparisons between short-term outcomes of OAB + MBP and MBP/no preparation were made using prospectively collected data on length of stay (LOS), readmission, mortality within 30 days, anastomotic leakage (AL), surgical site infection (SSI), urinary tract infection, deep venous thrombosis and/or pulmonary embolism, pneumonia, and ileus. Follow-up was limited to hospital stays and subsequent presentations within the health district within thirty days of surgery. The Mann–Whitney U test was used to analyse continuous data, and the chi-square test was used for categorical data. Univariate and multivariate regression modelling was performed to identify risk factors associated with an increased likelihood of SSI and AL. Results: Patients with oral neomycin and metronidazole combined with bowel preparation had reduced superficial SSI (2.7% vs. 7.6%, p = 0.043) and overall complications (32.7% vs. 44.6%, p = 0.020), particularly Clavien–Dindo 1 complications (7.3% vs. 16.5%, p = 0.009). However, the differences in AL (2.7% vs. 4.5%, p = 0.369) and organ/space SSI (1.3% vs. 3.7%, p = 0.327) were not statistically significant. The median LOS (6 d vs. 6 d, p = 0.370) was not different between the groups. Conclusion: Selective decontamination with neomycin and metronidazole reduces the risk of SSIs and overall complications. There was a trend to toward a lower AL, but this difference was not statistically significant.