The relationship between lipid-lowering drugs and the risk of digestive system cancers remains unclear. This study aims to assess the risk association between lipid-lowering drugs and digestive system cancers through mendelian randomization (MR) analysis. We utilized genetic instruments to substitute for the exposure to lipid-lowering drugs, including expression quantitative trait loci (eQTL) for HMGCR, PCSK9, and NPC1L1, as well as genetic variants associated with low-density lipoprotein (LDL) from the Global Lipids Genetics Consortium's genome-wide association study (GWAS) data for target genes. We used MR and SMR methods to assess the risk estimates of lipid-lowering drug target genes on digestive system tumors. The MR analysis indicated a negative association between HMGCR-mediated LDL and hepatocellular carcinoma (OR = 0.06, 95% CI: 0.00-0.81,  = 0.03), and a positive association between NPC1L1-mediated LDL and gastric cancer risk (OR = 15.45, 95% CI: 5.96-40.56,  < 0.01). In the SMR analysis, it was observed that HMGCR expression decreased the risk of hepatocellular carcinoma (OR = 0.11, 95% CI: 0.02-0.68,  = 0.02), while NPC1L1 expression increased the risk of gastric cancer (OR = 1.33, 95% CI: 1.08-1.64,  < 0.01). Our study results suggested a potential risk association between HMGCR inhibitors and NPC1L1 with hepatocellular carcinoma and gastric cancer.