Deltamethrin is a commonly applied pyrethroid insecticide; however, its relationship with the risk of coronary heart disease (CHD) remains unclear. Given its widespread residues in the environment and food, and the growing concern over its long-term cardiovascular effects, it is of public health importance to determine whether and how deltamethrin exposure contributes to CHD. This study integrated data from the Global Burden of Disease study (GBD 2021) and Mendelian randomization (MR) to assess causality. Utilizing transcriptomic data associated with CHD and the predicted targets of deltamethrin, core genes were identified through weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, and machine learning, pinpointing SPI1, IL1B, ICAM1 and FCER1G. These genes were enriched in immune-inflammatory pathways, associated with a pro-inflammatory microenvironment, and showed specific expression in monocytes. Molecular docking and dynamics simulations confirmed stable binding of deltamethrin to these targets. In vitro experiments demonstrated that deltamethrin dose-dependently inhibited cell viability, induced oxidative stress, and upregulated the expression of the core genes. In conclusion, deltamethrin may increase the risk of CHD, possibly by disrupting the immune-inflammatory networks involving SPI1, IL1B, ICAM1 and FCER1G, providing novel insights into the cardiovascular toxic effects of pyrethroids.