Technological advancements in minimally invasive surgery have led to significant improvements in patient outcomes. One such technology is surgical stapling, which has evolved into a key component of many operating rooms by facilitating ease and efficacy in resection and repair of diseased or otherwise compromised tissue. Despite such advancements, adverse post-operative outcomes such as anastomotic leak remain a persistent problem in surgical stapling and its correlates (i.e., hand-sewing), most notably in low colorectal or coloanal procedures. Many factors may drive anastomotic leaks, including tissue perfusion, microbiome composition, and patient factors such as pre-existing disease. Surgical intervention induces complex acute and chronic changes to the mechanical environment of the tissue; however, roles of mechanical forces in post-operative healing remain poorly characterized. It is well known that cells sense and respond to their local mechanical environment and that dysfunction of this “mechanosensing” phenomenon contributes to a myriad of diseases. Mechanosensing has been investigated in wound healing contexts such as dermal incisional and excisional wounds and development of pressure ulcers; however, reports investigating roles of mechanical forces in adverse post-operative gastrointestinal wound healing are lacking. To understand this relationship well, it is critical to understand: 1) the intraoperative material responses of tissue to surgical intervention, and 2) the post-operative mechanobiological response of the tissue to surgically imposed forces. In this review, we summarize the state of the field in each of these contexts while highlighting areas of opportunity for discovery and innovation which can positively impact patient outcomes in minimally invasive surgery.