The status of fatigue, depression, and activities of daily living and their relationships with cognitive function in patients with neuromyelitis optica (NMO) after acute relapse has never been observed. This study investigated cognitive function, fatigue, depression, activities of daily living, and the relationships among them in NMO patients. Twenty-two NMO patients without visible lesions on conventional brain MRI after acute relapse, 22 depression patients, and 22 healthy comparison subjects received several scales to assess cognitive function, fatigue, and depression. Every NMO patient completed a survey of activities of daily living. Between-group comparisons and correlational analyses were applied to examine the differences and the relationships among them. We found that NMO patients had significantly impaired memory, decreased information processing speed, and damaged attention. Some impaired cognitive domains were significantly correlated with fatigue and depression, and activities of daily living were correlated with these impaired cognitive domains, fatigue, depression, and disability. These results confirm cognitive deficits in memory, information processing speed, and attention exist in NMO patients without visible brain lesions after acute relapse. Fatigue and depression may affect cognitive function and increase the negative impact of cognitive deficits on the activities of daily living in patients with NMO.