Dyslipidemia is one of the most common chronic conditions managed in primary care, and long-term preventive strategies are essential to reduce both cardiovascular and cancer-related morbidity. While statins are widely used, the potential broader benefits of adding ezetimibe—particularly regarding cancer prevention—remain unclear in routine practice. As combination therapy is increasingly initiated in primary care settings, evidence on its long-term impact on cancer outcomes is needed to guide clinical decision-making.To evaluate whether ezetimibe–statin combination therapy is associated with a lower long-term risk of cancer compared with statin monotherapy in a real-world primary care population, and to explore potential biological mechanisms supporting this association.A retrospective cohort study was performed using the Korean National Health Insurance Service–National Sample Cohort. Adults newly diagnosed with dyslipidemia were categorized into statin monotherapy, ezetimibe–statin combination therapy, and non-user groups. Propensity score matching was used to balance baseline characteristics. Cox proportional hazards models estimated cancer incidence, and subgroup analyses were conducted by age, sex, and diabetes status. To assess biological plausibility, Dependency Map (DepMap) analyses and in vitro proliferation assays were conducted focusing on Niemann–Pick C1-Like 1 (NPC1L1).Among 104,212 individuals, ezetimibe–statin combination therapy was associated with a substantially lower risk of overall cancer compared with statin monotherapy (approximately 50% relative risk reduction). The association was strongest for digestive organ cancers, including liver, gastric, and gastro-esophageal cancers. Findings were consistent across sex, age, and metabolic subgroups. Experimental analyses showed reduced cancer cell viability with NPC1L1 knockdown and greater antiproliferative effects with combination therapy versus statin alone.Ezetimibe–statin therapy was associated with a meaningful reduction in long-term cancer incidence, with the strongest effects observed in gastrointestinal cancers. The consistency of results across subgroups and the biological plausibility supported by NPC1L1-related experimental data suggest that the benefit may extend beyond cholesterol lowering. These findings highlight the potential preventive value of combination therapy in real-world primary care settings.Ezetimibe–statin therapy showed lower long-term cancer risk than statins alone, suggesting potential preventive value in primary care.