BACKGROUND: Encephalopathy is reported to have affected 250,000 people . one United States over the last decade, with considerable morbidity and mortality. Baclofen, a gamma-aminobutyric acid-B agonist that acts on the central nervous system, is the drug most widely used to treat spasticity. Baclofen overdose is a potentially deadly condition that can cause encephalopathy and can result from multiple etiologies. Renal disease can contribute to baclofen overdose and encephalopathy, and there are currently no dosing recommendations for patient's on baclofen with renal impairment. CASE DESCRIPTION: We report an unusual case of a man aged 35 years who presented with persistent fevers, seizures, and normal mentation. The patient presented with intrathecal baclofen use and prior exposure to West Nile Virus. He developed acute kidney injury at hospital secondary to vancomycin use, and mental status declined. CONCLUSIONS: This case highlights that patients with baclofen overdose initially appear to have serious brain injury, however, full patient recovery can occur in <72 hours. This case provides additional insight into the guidelines for the treatment and management for unknown cause encephalopathy. This case also highlights the link between renal disease, baclofen, and encephalopathy through a review of the literature.