BACKGROUND: Acute necrotizing encephalopathy is a rare, clinically distinct subgroup of acute encephalopathy, which may be a complication of coronavirus disease 2019. CASE PRESENTATION: A 22-year-old male of Han Chinese with a yellow complexion presented with fever, psychological and behavioral abnormalities, seizures, and coma. Cerebrospinal fluid tests indicated leukocytosis, high protein concentrations, and significantly elevated levels of neuron-specific enolase, interleukin-2, interleukin-6, and interleukin-8. Magnetic resonance imaging revealed restricted diffusion in the bilateral thalami and splenium of the corpus callosum, and no hemorrhagic signals were detected on susceptibility-weighted imaging. Hyperintense and hypointense lesions in the bilateral thalami, brainstem, cerebellum, and splenium of the corpus callosum were observed in T1- and T2-weighted sequences without gadolinium enhancement. At the 6-month follow-up, the T1 and T2 sequences showed significant atrophy in the cerebellar hemispheres and brachium pontis and an enlarged fourth ventricle. After symptomatic and immunotherapy treatment, the prognosis was good. CONCLUSION: We report a rare case of a 22-year-old male diagnosed acute necrotizing encephalopathy showing typical imaging findings and distinctive cerebrospinal fluid presentation. In adults, heightened awareness of acute necrotizing encephalopathy is crucial because early recognition and treatment have the potential to enhance prognosis.