Orofacial pain represents a challenge for dentists, especially if it does not have an odontogenic origin. Orofacial neuropathic pain may be chronic, is arduous to localize and may develop without obvious pathology. Comorbid psychiatric disorders, such as anxiety and depression, coexist and negatively affect this condition. This article presents one case of atypical odontalgia and one of trigeminal neuralgia treated with psychological and psychopharmacological tailored and adapted therapies, after conventional medications had failed. Additionally, an overview of the pathologies related to the challenging differential diagnosis in orofacial pain is given. A 68-year-old man complained of chronic throbbing and burning pain in a maxillary tooth, which worsened upon digital pressure. Symptoms did not abate after amitriptyline therapy; psychological intervention along with antianxiety drug were supplemented and antidepressant agent dosage were incremented. The patient reported improvement and satisfaction with the multidisciplinary approach to his pathology. A 72-year-old man complained of chronic stabbing, intermittent, sharp, shooting and electric shock-like pain in an upper tooth, radiating and following the distribution of the trigeminal nerve. Pain did not recur after psychological intervention and a prescription of antidepressant and antianxiety agents, while carbamazepine therapy had not been sufficient to control pain. Due to concerns with comorbid psychiatric disorders, we adopted a patient-centered, tailored and balanced therapy, favorably changing clinical outcomes. Comorbid psychiatric disorders have a negative impact on orofacial pain, and dentists should consider adopting tailored therapies, such as psychological counselling and behavioral and psychopharmacologic strategies, besides conventional treatments. They also must be familiar with the signs and symptoms of orofacial pain, obtaining a comprehensive view of the pathologies concerning the differential diagnosis. A prompt diagnosis may prevent pain chronicity, avoiding an increase in complexity and a shift to orofacial neuropathic pain and legal claims.