Isolated hypoglossal nerve paresis due to mechanical compression from a vascular lesion is very rare. We present a case of a 32-year-old man who presented with spontaneous abrupt-onset dysarthria, swallowing difficulty and left-sided tongue atrophy. Brain computed tomographic angiography and magnetic resonance imaging of the brainstem demonstrated an abnormal course of the left vertebral artery compressing the medulla oblongata at the exit zone of the hypoglossal rootlets that was relieved by microvascular decompression of the offending intracranial vertebral artery. This case supports the hypothesis that hypoglossal nerve palsy can be due to nerve stretching and compression by a pulsating normal vertebral artery. Microvascular decompression of the intracranial nerve and careful evaluation of the imaging studies can resolve unexpected isolated hypoglossal nerve palsy.