Sarcopenia is a syndrome characterized by a progressive, widespread decline in muscle mass and strength. DEHP, a plasticizer involved in daily life and widely used, has been found in various everyday items and causes developmental dysregulation, reproductive impairments, tumorigenesis, and transgenerational disease. However, much remains to be discovered regarding the association between exposure to this environmental toxin and sarcopenia, as well as the toxic targets and molecular mechanisms. This research elucidated the relationship between contact with DEHP and the development of sarcopenia by integrating NHANES data analysis, network toxicology, and molecular docking. 3199 adults were enrolled, and multiple linear regressions were performed to reveal a significant negative correlation between lnDEHP and ALMBMI. Eighty-eight targets associated with DEHP and sarcopenia were identified. Subsequent STRING and Cytoscape screening stressed 20 key targets, including CASP3, BCL2, MMP9, BCL2L1, APP, and CTSS. GO and KEGG enrichment analyses revealed that these targets are involved in ligand-receptor interactions, apoptosis, and calcium signaling pathways. Molecular docking simulations using CB-dock confirmed the high-affinity binding interactions between DEHP and these key targets. This study validated the relationship between DEHP exposure and muscle mass. Further, it provided a theoretical basis for investigating the molecular mechanisms of DEHP exposure-induced skeletal muscle toxicity.Copyright © 2025. Published by Elsevier Inc.