No reported cases to date describe herpes simplex virus (HSV) myelitis in association with cancer and chemo-radiation. We report a case of sub-acute HSV myelitis in a 54-year-old man receiving chemo-radiation with 5-flourouracil for esophageal cancer who presented to the emergency department with increasing numbness in both lower limbs that gradually spread to waist level. Magnetic resonance imaging with gadobutrol contrast 1 week later showed transverse myelitis involving the dorsal columns. Radiation-induced myelitis was suspected, and the patient was initially treated with dexamethasone; however, CSF analysis revealed HSV myelitis. Treatment with antivirals resolved much of the numbness. HSV myelitis can be confused with complications of radiation or malignancy in patients presenting with focal neurological deficits.