Background: Lipid metabolism plays an important role in the pathogenesis and development of calcific aortic valve stenosis. Our aim was to evaluate the causal effect of lipid-lowering drugs, such as low-density lipoprotein cholesterol (LDL-C) lowering and triglyceride lowering drugs, on the outcome of aortic valve stenosis using a two-sample Mendelian randomization (MR) study. Methods: We used two genetic tools to represent the exposure of lipid-lowering drugs, including expression quantitative trait loci for the expression of drug target genes, and genetic variants within or near drug target genes that are associated with LDL-C and triglyceride concentrations from Genome-Wide Association Studies (GWAS). Effect estimates were calculated using summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis. Results: Based on the results of SMR and IVW-MR analysis, LDL-C-lowering PCSK9 inhibitors have potential in reducing the risk of aortic valve stenosis (for SMR, OR: 1.044; 95%CI: 1.002–1.404; P = 0.047; for IVW-MR, OR: 1.647, 95%CI: 1.316–2.062, P < 0.001). However, no significant association was observed between triglyceride target gene expression, as well as triglyceride-lowering drugs, and aortic valve stenosis. Conclusion: This two-sample drug-targeted MR study suggests a potential causal relationship between PCSK9 inhibitors and the reduction of calcific aortic valve stenosis risk.