Anastomotic leak after colorectal surgery is a devastating complication that may require re-operation, diverting stoma creation, and prolonged wound healing. Anastomotic leak is associated with a mortality of 4% to 20%. Despite intense research and novel approaches, the anastomotic leak rate has failed to substantially improve over the past decade. Adequate anastomotic healing requires collagen deposition and remodeling through post-translational modification. The human gut microbiome has been previously implicated as a key driver of wound and anastomotic complications. Specific microbes function in a pathogenic fashion by propagating anastomotic leak and poor wound healing. The two most studied organisms, Enterococcus faecalis and Pseudomonas aeruginosa , can be collagenolytic and may activate additional enzymatic pathways that lyse connective tissue. Furthermore, these microbes are enriched in post-operative anastomotic tissue as identified using 16S rRNA sequencing. Commonly encountered stressors including antibiotic administration, a Western (i.e., high-fat, low-fiber) diet, and concomitant infection can trigger dysbiosis and induce a pathobiome phenotype. Therefore, personalized microbiome modulation to maintain homeostasis may be the next step in improving the anastomotic leak rate. Oral phosphate analogs, tranexamic acid, and pre-operative diet rehabilitation have shown promise in in vitro and in vivo studies as ways to address the pathogenic microbiome. However, further translational human studies are required to validate findings. Accordingly, this article reviews the gut microbiome as it pertains to post-operative anastomotic leak, explores microbial impact on anastomotic healing, describes the shift from the commensal microbiome to a pathobiome, and introduces potential therapies to mitigate anastomotic leak risk.