This case series presents two cases of acute acalculous cholecystitis (AAC)—a rare condition—in young women with central nervous system (CNS) lesions. Both patients had significant neurologic deficits and no well-known risk factors or presence of comorbidities (such as diabetes or a history of cardiovascular or cerebrovascular disease). Early diagnosis is important in cases of AAC owing to its high mortality rate; however, due to neurological deficits in our cases, accurate medical and physical examinations were limited, thereby leading to a delay in the diagnosis. The first case was of a 33-year-old woman with multiple fractures and hypovolemic shock due to a traumatic accident; she was diagnosed with hypoxic brain injury. The second case was of a 32-year-old woman with bipolar disorder and early-onset cerebellar ataxia who developed symptoms of impaired cognition and psychosis; she was later diagnosed with autoimmune encephalopathy. In the first case, the duration between symptom onset and diagnosis was 1 day, but in the second case, it was 4 days from diagnosis based on the occurrence of high fever. We emphasize that if a young woman presents with high fever, the possibility of AAC should be considered, particularly if a CNS lesion is present because it may pose difficulty in the evaluation of typical symptoms of AAC. Careful attention is thus required in such cases.