Abstract: Objective: To investigate the association between plasma proteins and coronary artery disease (CAD) risk using data from the UK Biobank. Methods: Cox proportional hazards models were applied to assess prospective associations of 2,911 proteins with CAD incidence. Pathway enrichment analysis was performed to identify relevant biological processes. Two-sample Mendelian randomization (MR) and colocalization analyses were conducted to infer causal relationships, and the clinical translational potential of key proteins was evaluated using DrugBank databases. Results: During a median follow-up of 14.52 years, 3,760 incident CAD cases were documented. A total of 508 proteins were identified to be significantly associated with the risk of CAD, and these proteins were enriched in atherosclerosis-related pathways. MR analysis confirmed 27 proteins with causal evidence for CAD. Colocalization analysis supported shared causal genetic variants between CAD and PCSK9/IFI30 proteins. Drug target validation indicated existing pharmacological development potential for several proteins. Conclusion: This study identifies key plasma proteins associated with CAD risk and demonstrates their causal roles, providing a theoretical foundation for elucidating disease mechanisms and developing early prediction models and precision treatment strategies.