Formation of a uterine niche following a C-section can predispose the patient to future obstetric complications such as dehiscence, uterine rupture, ectopic pregnancy, and placenta accreta. The significant morbidity and mortality of these complications along with increasing C-section rates emphasizes the importance of prevention. However, there are no clear guidelines on intra-operative protocol to prevent postpartum niche formation. Besides surgical technique, the novel use of platelet-rich plasma (PRP) and mesenchymal stem cell (MSC) injections has demonstrated promising potential and may have applications in hysterotomy closures. The objective is to examine current research on optimal C-section procedures to prevent uterine niche formation and subsequent obstetric complications. A systematic review was conducted using PubMed and Google Scholar. Initial searches yielded 827 results. Inclusion criteria were human, animal, and in-vitro studies, peer-reviewed sources, and outcomes pertinent to the uterine niche. Exclusion criteria applied to articles with outcomes unrelated to myometrium and interventions outside of the intra-operative and immediate pre-/post-operative period. Based on the criteria, 41 articles were cited. Pathophysiology of uterine niche formation was associated with incisions through cervical tissue, adhesion formation, and poor approximation. Significant risk factors were low uterine incisions, advanced cervical dilatation, low station, non-closure of the peritoneum, and creation of a bladder flap. There was no consensus on uterine closure as it likely depends on surgical proficiency with the given technique, but a double-layered non-locking suture appears reliable to reduce niche severity. Recent trials indicate that intra-operative PRP/MSC injections may decrease niche incidence and severity, but more research is needed. If prevention or minimization of uterine niche is desired, the optimal C-section protocol should avoid low uterine incisions, choose uterine closure technique based on the surgeon's proficiency (double-layered non-locking is reliable), and close the peritoneum, and myometrial injection of PRP/MSC may be a useful adjunct intervention pending further clinical evidence.