Aortic dissection (AD) is a life-threatening acute aortic syndrome. There are limitations and challenges in the discovery and application of biomarkers and drug targets for AD. Mendelian randomization (MR) analysis is a reliable analytical method to identify effective therapeutic targets. We aimed to identify novel therapeutic targets for AD and investigate their potential side-effects based on MR analysis. Data from protein quantitative trait loci (pQTLs) were used for MR analyses to identify potential therapeutic targets. We probed druggable proteins involved in the pathogenesis of aortic dissection from deCODE. In this study, a two-sample MR analysis was conducted, with druggable proteins as the exposure factor and data on genome-wide association studies (GWAS) of AD as the outcome. After conducting a two-sample MR, summary data-based Mendelian randomization (SMR) analysis and colocalization analysis were performed. A protein–protein interaction (PPI) network was also constructed to delve into the interactions between identified proteins. After MR analysis and the Steiger test, we identified five proteins as potential therapeutic targets for AD. SMR analysis and colocalization analysis also confirmed our findings. Finally, we identified ASPN (OR = 1.36, 95% CI: 1.20, 1.54, p = 4.22 × 10⁻⁵) and SPOCK2 (OR = 0.57, 95% CI: 0.41, 0.78, p = 4.52 × 10⁻⁴) as the core therapeutic targets. Through PPI network analysis, we identified six druggable targets, enabling the subsequent identification of six promising drugs from DrugBank for treating AD. This discovery of specific proteins as novel therapeutic targets represents a significant advancement in AD treatment. These findings provide more effective treatment options for AD.