A 47-year-old woman with a history of substance abuse, depression, and insomnia experienced a collapse. Upon arrival at the hospital, the patient displayed low systolic blood pressure, confusion, dehydration, and renal failure. Urine tests confirmed an amphetamine and opioid overdose. Her condition fluctuated with reduced consciousness, myoclonic movements, fever, and suspected psychogenic seizures. Brain magnetic resonance imaging revealed abnormalities in the splenium of the corpus callosum, which later resolved. The patient's condition gradually improved without any specific treatment. This unique case represents the first report of mild encephalopathy/encephalitis with reversible splenial lesions associated with amphetamine and opioid use.