Purpose: The efficacy of Seprafilm® in preventing clinically significant adhesive small bowel obstruction (ASBO) is controversial and deserves further review. The aim of this review was to assess the utility of Seprafilm® in preventing clinically significant adhesive bowel obstruction after gastrointestinal operations, with particular focus on colorectal resections. The secondary aim was to provide an updated literature review on the safety profile of this implant. Methodology: An up-to-date systematic review was performed on the available literature between 2000–2023 on PubMed, EMBASE, Medline, and Cochrane Library databases. The main outcome measures were rates of adhesive bowel obstruction, as well as rates of intervention. The secondary outcome was the clinical safety profile of Seprafilm® as described in current literature. Results: A total of 17 observational studies were included, accounting for 62,886 patients. Use of Seprafilm® was associated with a significant reduction in adhesive bowel obstruction events (OR 0.449, 95% CI: 0.3271 to 0.6122, p < 0.001), with preserved efficacy seen in laparoscopic cases. This did not translate into a reduced rate of reintervention. Clinicians should also be aware of isolated reports of a paradoxical inflammatory reaction leading to fluid collections after Seprafilm® use, although they appear uncommon. Conclusion: Seprafilm® can be considered in select patients although further study to determine which patients will benefit most is required.