Background: Reversible splenial lesion syndrome (RESLES) is a rare clinico-radiological entity associated with multiple etiologies including infection, metabolic, and epileptic disorders. We describe the case of a child with a reversible splenial lesion who presented with encephalopathy and prior history of episodic ataxia. Methods: A 3-year-old girl presented to the Stollery Children’s hospital with three days of respiratory symptoms followed by acute onset ataxia and encephalopathy. Blood, respiratory samples, and cerebral spinal fluid (CSF) were drawn to investigate for infectious, autoimmune, and metabolic causes. Magnetic resonance imaging (MRI) brain was done and repeated. Results: A respiratory panel tested positive for respiratory syncytial virus (RSV), enterovirus, and rhinovirus. CSF analysis revealed elevated white blood cell count (283). MRI brain demonstrated diffusion restriction involving the posterior body and splenium of the corpus callosum and bilateral middle cerebral peduncles, which resolved nine days later. The patient received high-dose steroids with gradual improvement in the encephalopathy and ataxia. Conclusions: This report contributes to the complexities in clinical understanding of RESLES, as it highlights a novel presentation with ataxia and encephalopathy. The patient’s diagnosis was complicated by previous ataxic episodes of unknown etiology, which allows further consideration of a metabolic or genetic ataxic syndrome and its relationship to encephalopathy.