Objective: The purpose of this study was to assess the causal effects of circulating plasma proteins on ankylosing spondylitis (AS) and to explore potential therapeutic targets. Methods: The study used protein quantitative trait loci (pQTLs) for thousands of plasma proteins from nine genome-wide association studies (GWAS) as instrumental variables. The relationship between genetically predicted plasma proteins and AS was assessed through Mendelian randomization (MR) analysis. Further analyses, including colocalization analysis, Steiger filtering analysis, protein-altering variant assessment, protein–protein interaction (PPI), and pathway enrichment analysis, were conducted to validate the robustness and causal direction of the results, as well as to investigate the protein functions and potential drug targets. Results: Nine unique proteins were found to have strong causal associations with AS. Steiger filtering analysis confirmed that all associations identified by MR analysis have a direct causal link from the proteins to AS. Colocalization analysis identified four unique proteins—Interleukin-6 receptor alpha (IL-6Rα), Interleukin-23 receptor (IL-23R), Thrombospondin-2 (THBS2), and Interleukin-1 receptor type 2 (IL-1R2)—that share the same causal variants with AS. PPI and pathway enrichment analysis revealed the potential roles of these proteins in inflammatory responses and immune regulation. Moreover, these proteins were valuable drug targets or considered druggable. Conclusions: This study has identified multiple plasma proteins associated with AS, revealing the important roles of these proteins in the pathogenesis of AS and providing potential therapeutic targets for AS.