Background: Ankylosing spondylitis (AS) is a rheumatic inflammatory disease with unknown etiology, and fatigue is one of the main systemic symptoms of AS. The aim of the current study was to explore the mechanism of AS-associated fatigue (ASF) from multiple aspects, including neuropsychological changes.Method: A total of 120 AS patients and 78 age- and sex-matched healthy individuals were recruited into the study. Fatigue was assessed by the fatigue item of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Multidimensional Assessment of Fatigue (MAF) scale. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). The cortical thickness and subcortical gray matter volume were assessed using a Philips Achieva 3.0 T TX MRI scanner.Result: Of the 120 AS patients, 103 (85.8%) reported varying degrees of fatigue. Among these fatigue cases, 33 (32.0%) were in the severe fatigue group (BASDAI-Fatigue ≥ 5), and 70 patients (68.0%) were considered to be in the mild fatigue group (BASDAI-Fatigue > 0 but <5). The BASDAI, ASDAS-CRP, HAD-A, and HAD-D scores of AS patients in the severe fatigue group were all significantly higher than those of patients in the mild fatigue and non-fatigue groups (all, P < 0.05). The structural equation model suggested that AS activity triggered the occurrence of fatigue by inducing psychological change. Finally, head MRI imaging found that the left thalamus volume in AS patients with severe fatigue was significantly larger than that in non-fatigue AS patients and healthy controls (both, P < 0.05).Conclusion: The study revealed neuropsychological factors involved in fatigue in AS.