Ankylosing spondylitis (AS) is a chronic inflammatory disorder with unknown etiology and hard to early diagnose. It’s imperative to investigate the changes in AS patients’ peripheral blood, which may contribute to the diagnosis and further understanding of AS. Common differential expressed genes between normal and AS patients in GSE73754 and GSE25101 were screened by machine learning algorithms. IL2RB and ZDHHC18 were hubgenes screened and a diagnostic model was established. C-indexes and calibration analyses suggested high prediction accuracy of the model in training and validation cohorts. The AUC values of the model in GSE73754, GSE25101, GSE18781 and GSE11886 were 0.86, 0.84, 0.85 and 0.89 respectively. Decision curve analyses suggested high net benefit by the model. Functional analysis of the differential expressed genes indicated that they were mainly clustered in processes related to immune response. Immune microenvironment analysis revealed that neutrophils were expanded and activated in AS, while some T cells were decreased. IL2RB and ZDHHC18 were potential blood biomarkers for AS and might be used for early diagnosis and a supplementary diagnostic tool to the existing methods. Our study deepened the insight into the pathogenesis of AS.