Background: Autoimmune diseases (ADs) have serious impacts on the quality of life of patients and for which with no ideal treatment. The plasma proteome represents a major source of druggable targets. We aimed to identify plasma proteins as potential therapeutic targets for ADs. Methods: We performed two-sample Mendelian Randomization (MR) to explore the causal relationship between 4,907 plasma proteins (N=35,559) and six ADs (N ranged from 23,210 to 173,981) and further validated using another independent plasma proteomic dataset (N=10,708). Five methods were used to evaluate the causal effects, including inverse variance weighted, MR egger, weighted median, simple mode and weighted mode. Sensitivity analysis and reverse MR analysis were conducted to evaluate the robustness of MR results and druggability analysis was used to identify potential drug targets. Results: A total of 24 plasma proteins associated with ADs were identified in the discovery dataset, of which 11 were successfully validated in replication sample. The genetically predicted ARC1B, FcRIIIa, MAPK2 and Collagen II were associated with type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease and celiac disease, respectively. The genetically predicted TBPL1 and DEFI6 were associated with systemic lupus erythematosus. IL-2 sRa, MICB, FTMT, FCAMR and SLAF1 were associated with multiple sclerosis. No reverse causation existed. The druggability analysis showed that IL-2 sRa has become an approved drug target and FcRIIIa and MAPK2 are in clinical trials. Conclusions: The identified proteins might be promising drug targets for ADs and warrant further mechanistic studies.