Wegener’s granulomatosis (WG) is a condition with immune-mediated pathogenesis that can present oral manifestations. This report describes the case of a patient diagnosed with WG 14 years previously, who was affected by persistent pain of non-odontogenic origin after successful endodontic treatment. A 39-year-old woman with WG was diagnosed with pulp necrosis and apical periodontitis of teeth #31, #32, and #41, after evaluation through a clinical examination and cone-beam computed tomography (CBCT). At the first appointment, these teeth were subjected to conventional endodontic treatment. At 6- and 12-month follow-up visits, the patient complained of persistent pain associated with the endodontically treated teeth (mainly in tooth #31), despite complete remission of the periapical lesions shown by radiographic and CBCT exams proving the effectiveness of the endodontic treatments, thus indicating a probable diagnostic of persistent pain of non-odontogenic nature. After the surgical procedure was performed to curette the lesion and section 3 mm of the apical third of tooth #31, the histopathological analysis suggested that the painful condition was likely associated with the patient's systemic condition. Based on clinical, radiographic, and histopathological findings, this unusual case report suggests that WG may be related to non-odontogenic persistent pain after successful endodontic treatments.