Orofacial granulomatosis is characterized by persistent or recurrent orofacial soft tissue enlargement and a microscopic granulomatous process. It may encompass granulomatous cheilitis of Miescher and Melkersson–Rosenthal syndrome, although most of the cases do not comply with these conditions. Granulomatous cheilitis is characterized by tissue swelling restricted to one or both lips, more often painless, non-pruritic, and with an acute onset and recurrent episodes, while Melkerson–Rosenthal syndrome represents a neuro-mucocutaneous disorder, showing orofacial edema, cranial nerve involvement, and fissured tongue, but this clinical triad is usually not simultaneously present or complete in all patients. A subset of orofacial granulomatosis has also been associated with Crohn’s disease; however, whether these conditions represent the same entity or distinct disorders remains to be further demonstrated. Microscopically, orofacial granulomatosis and Crohn’s disease are characterized by non-caseous granulomatous inflammation, and differential diagnosis includes granulomatous inflammatory reactions associated with infectious agents, foreign body reactions, and sarcoidosis. Different therapeutic methods have been used for treating orofacial granulomatosis, more often encompassing the use of steroids, either locally or systemically, associated or not with immunosuppressants. Treating intestinal disorders is mandatory for those patients affected by Crohn’s disease.