Background and Clinical Significance: Orofacial granulomatosis is a rare but often disabling condition potentially associated with inflammatory bowel disease (IBD). Pathogenesis is not well understood, and no disease-specific approved treatments exist to date. Case presentation: A 26-year-old woman with pan-enteric Crohn's disease developed buccal swelling and deep oral ulcers histologically confirmed as associated orofacial granulomatosis. Multiple therapies were attempted during her life, including systemic steroids and immunomodulator drugs as Thalidomide, Adalimumab, and Ustekinumab in combination with topical steroid injections and Cyclosporin application, with no or minimal benefit. Only Infliximab showed good efficacy, but it was suspended due to side effects. Following secondary loss of response to Ustekinumab, compassionate treatment with Upadacitinib, a recently developed oral Jak-1 selective inhibitor, resulted in complete resolution of the oral ulcers. Moreover, after the 12-week induction phase and the transition to 30 mg/daily maintenance dosage, the oral disease remained controlled. Due to clinical recurrence of Crohn’s disease, Vedolizumab was added as associated treatment, resulting in complete clinical benefit after six-months follow-up. Conclusions: This is a unique case of oro-facial granulomatosis associated with panenteric Crohn’s disease successfully treated with Upadacitinib. Larger data are needed to explore its potential benefits in this clinical condition.