Mild encephalopathy/encephalitis with a reversible splenial lesion (MERS) and longitudinally extensive transverse myelitis (LETM) are neuroinflammatory conditions related to the brain and spinal cord, respectively. Most cases of MERS and LETM are related to a secondary autoimmune process in response to an initial insult (i.e., infection, immunization, etc.). The case of an 18-year-old female who developed a three-day history of fever, quadriplegia, cough, and mild encephalopathy is reported here. The patient tested positive for influenza B by nasopharyngeal swab with polymerase chain reaction (PCR). Initial magnetic resonance imaging (MRI) revealed the presence of a diffusion-restricted non-enhancing lesion confined to the splenium of the corpus callosum (MERS type I) and longitudinally extensive non-enhancing T2 hyperintensities from C1 to C5. The patient was managed with a five-day course of 1,000 mg of intravenous methylprednisolone (IVMP). Additionally, five days of therapeutic plasmapheresis (PLEX) was completed. The patient showed significant improvement with medical management and physical therapy. At the one-year follow-up, her motor symptoms had resolved and endorsed only mild paresthesia in the upper extremities. A repeat MRI revealed a reversal of the splenium lesion and moderate improvement in T2 hyperintensities of the cervical cord. Assessing neuroinvasion of the influenza virus is difficult, and diagnostic challenges arise in determining primary infectious versus autoimmune-mediated neuroinflammation. A review of the literature on influenza infection with radiographic findings of MERS and LETM is included.