Both hypertensive and breast diseases impose a significant societal burden. However, the correlation between antihypertensive drug use and breast cancer remains controversial. We aimed to determine their potential correlations and explore their possible mechanisms. We performed summary data-based Mendelian Randomization (SMR) analysis of expression quantitative trait loci (eQTL) data from the blood of patients with breast diseases. We then performed drug-targeting Mendelian Randomization (MR) analysis using blood pressure-related single nucleotide polymorphism (SNPs) as instrumental variables (IVs). False discovery rate (FDR) correction was performed for reliable results, and colocalization analysis was performed to clarify shared gene variants. Mediation MR methods were used to investigate the mechanistic pathways involved in this association. Combined with the results of SMR analysis and drug-targeting MR analysis, loop diuretics aggravated overall breast cancer (OR_SMR = 0.842, 95% CI_SMR: 0.778-0.911, P_SMR_FDR = 0.008) and ER + breast cancer (OR_SMR = 0.854, 95% CI_SMR: 0.778-0.937, P_SMR_FDR = 0.008) within SLC12A2 gene loci. Colocalization analysis showed that SLC12A2-targeted drugs share a common variant site with breast cancer. Mediation analyses suggested that the pathway related to intestinal ischemia mediated 73.711% of the total effect on over breast cancer risk in the SLC12A2 gene loci. Antihypertensive drugs increase the overall risk of breast cancer and ER + breast cancer within the SLC12A2 gene. And overall breast cancer risk which may result from intestinal ischemia. Given the long-term safety of antihypertensive drugs, significance should be attached to the prevention and early detection of breast cancer in patients taking loop diuretics.