BACKGROUND: Large incisional hernias in high-risk patients, such as those undergoing immunosuppressive therapy, represent an extra surgical challenge due to elevated risks of infection and poor wound healing. This case report details the reconstruction of an abdominal wall defect in a high-risk patient using a high-cost yet robust and effective biologic mesh. CASE PRESENTATION: A 38-year-old obese female with multiple comorbidities developed an LIH and an incarcerated left-sided inguinal hernia following a kidney transplantation. The surgical approach involved a two-layer mesh reconstruction, combining a biologic intraperitoneal mesh and an absorbable onlay mesh. To reduce the risk of infection and provide extra reinforcement, the hernia sac was preserved and sutured over the biologic mesh. Postoperative complications, including infection and seroma formation, were managed effectively with negative pressure wound therapy. The wound closed after seven months, with no recurrence observed during follow-up. DISCUSSION: The biologic mesh, combined with the well-vascularized sac, demonstrated integration with vascularized tissue, minimizing infection risk, and providing natural reinforcement and enhanced healing. Advanced wound management, including negative pressure wound therapy, effectively resolved postoperative complications such as infection and seroma. CONCLUSION: This case demonstrates the use of a multilayer reconstruction approach that combines a biologic mesh and the reuse of the hernia sac, offering a viable option for managing complex hernias in high-risk, immunosuppressed patients. This technique minimizes infection risk and provides stable long-term outcomes, even in challenging clinical settings.