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Giant inguinoscrotal hernias (GISHs) are rare and present unique surgical challenges. We report a case of a man in his 60s with a GISH complicated by loss of domain, with nearly two-thirds of the small bowel and right colon incarcerated in the inguinoscrotal hernia sac. A comprehensive preoperative plan was implemented, including botulinum toxin injections, placement of an inferior vena cava filter and progressive preoperative pneumoperitoneum per a locally developed protocol. A combined surgical approach was used, involving laparotomy, scrotal reconstruction, adhesiolysis, right hemicolectomy with omentectomy and Rives-Stoppa mesh repair extending into the retropubic space. A suture closure of the inguinal ligament to the pectineal line was performed with a Phasix Mesh. Plastic surgical techniques were employed to reduce scrotum size and reconstruct the penis. This case demonstrates the importance of a multimodal perioperative and surgical approach to manage GISHs to achieve optimal surgical outcomes.