Clinical guidelines recommend the use of statins to reduce portal pressure and alleviate portal hypertension (PH). However, there is a lack of population-level studies on the use of non-statin Low-Density Lipoprotein Cholesterol (LDL-c) reduction agents for the treatment of PH. This study utilized a novel method, Mendelian Randomization (MR) analysis, to investigate the impact of commonly used LDL-c-lowering medications on PH. Instrumental variables (IVs) for eight lipid-lowering drug-related genes were extracted from three large-scale LDL-c databases of Genome-Wide Association Studies (GWAS), followed by MR analysis. The MR results indicated that, compared to normal individuals, lower expression of CETP and NPC1L1 in whole blood (result of meta-analysis: CETP [OR: 0.322, 95%CI:0.130-0.795, P = 1.396e-02], NPC1L1 [OR: 0.057, 95%CI: 0.022-0.146, P = 2.670e-09]) is associated with reduced portal pressure. The IVs of target genes were subjected to MR analysis with coronary atherosclerosis (CAD) as a positive control, confirming that the IVs can effectively substitute for the biological function of the target gene, thereby further enhancing the reliability of the results. Subsequently, Summary-based Mendelian Randomization (SMR) analysis was conducted by using expression quantitative trait loci (eQTL) data to validate the results of the MR analysis. The SMR results suggested that only NPC1L1 is associated with PH (OR: 0.648, 95%CI: 0.472-0.891, P = 7.502e-3, P = 0.747) from genetic correlation. Additionally, mediation analysis indicates that the therapeutic effect of NPC1L1 inhibitors on PH is partially mediated by tissue factor (mediating effect accounted for 18.52%, and the P value was 0.01). Phenome-Wide MR indicated that NPC1L1 inhibitors may be associated with 23 diseases or symptoms. In addition, NPC1L1 had genetic correlation between and alkaline phosphatase as well as total bilirubin, but no genetic correlation with alanine aminotransferase, aspartate aminotransferase, direct bilirubin, or gamma glutamyltransferase. In conclusion, this study systematically analyzed the genetic correlation between lipid-lowering drug targets and PH. From a genetic correlation perspective, we revealed that the potential therapeutic effect of NPC1L1 on PH may not be mediated through the reduction of LDL-c but rather through the modulation of tissue factors. Additionally, the potential side effects associated with NPC1L1 inhibition also were explored.