Isolated occipital condyle lesions are commonly treated with empirical radiation, with the sole aim of relieving symptoms. Patients rarely undergo surgical biopsy, considering the morbidity associated with open surgery approaches and the importance of surrounding structures limiting the application of computed tomography (CT) scan or fluoroscopic percutaneous needle biopsies. We describe the case of a 66-year-old woman who was admitted on an emergency basis. Her clinical presentation included unilateral occipital headache and ipsilateral hypoglossal nerve palsy. Imaging revealed findings consistent with an isolated right occipital condyle lesion. In order to pursue a tissue diagnosis, essential to dictate medical management accurately, a minimally invasive biopsy of the occipital condyle through the trans-oral route was performed. Combined fluoroscopy, cone-bean CT and angiography allowed safe access to the lesion.