BACKGROUND: Despite significant advances in the therapeutic management of Crohn's disease (CD), a subset of patients remains refractory to available treatments. Dual-targeted therapy (DTT), combining biologics or biologics with small molecules, has emerged as a promising approach. While evidence supporting DTT continues to grow, reports of patients treated with a combination of 3 biologic or targeted agents remain exceptionally rare. CASE PRESENTATION: We report the case of a 30-year-old male with a complex clinical course, initially diagnosed with ulcerative colitis and later reclassified as CD following ileal pouch-anal anastomosis, due to subsequent small bowel and perianal involvement. The patient also had concomitant ankylosing spondylitis. Despite multiple lines of therapy, including, anti-tumor necrosis factor agents, vedolizumab, ustekinumab, and upadacitinib, both CD and ankylosing spondylitis remained clinically active. In the absence of alternative therapeutic options and continued refusal of surgery, a triple combination of certolizumab pegol, ustekinumab, and vedolizumab was initiated and maintained over 10 months. While the treatment was well tolerated and ankylosing spondylitis remained in remission, no impact was observed on CD. DISCUSSION: This case highlights the challenges of managing refractory inflammatory bowel disease with overlapping immune-mediated conditions. Although the combination of biologics targeting distinct inflammatory pathways is conceptually appealing and supported by emerging data on DTT, the effectiveness of triple therapy remains uncertain in some patients. CONCLUSIONS: Triple biologic therapy remains experimental and should be approached with caution, pending more robust evidence. Larger and translational studies are needed to better identify patients who may benefit, define optimal combinations, and clarify long-term safety of these combinations.