Deep incisional and organ/space surgical site infections (SSIs) after colorectal surgery are associated with adverse outcomes. Multiple antibiotic regimens are recommended for peri-operative prophylaxis, with no particular regimen preferred over another. We compared the prophylaxis regimens used in patients with and without SSIs, and the impact of regimens on the flora involved in SSIs. Information was extracted from the National Healthcare Safety Network databank of patients undergoing colorectal surgery from 2015 to 2022 in a large public healthcare system in New York City. Patients with SSIs were identified, and controlling for nine variables, propensity score matching was used to create a matched control group without SSIs. Prophylactic regimens were compared between the matched groups with and without SSIs. Also, for the patients with SSIs, the impact of the prophylactic regimen on the subsequent pathogens involved the infection was examined. A total of 275 patients with SSIs were compared to a matched cohort without SSIs. The prophylactic regimens were extremely similar between the SSI and control groups. Among the patients who developed SSIs, more patients who received cefoxitin had emergence of select cephalosporin-resistant Enterobacterales and Bacteroides spp. when compared with those who received β-lactam-β-lactamase inhibitors. The distribution of surgical prophylaxis regimens was remarkably similar between patients developing serious SSIs and a closely matched cohort that did not develop an SSI. However, given the downstream effects of more resistant and anaerobic flora should an infection develop, use of cefoxitin should be re-evaluated as a prophylactic agent.