Abstract: Microplastic pollution has emerged as a global environmental and health concern. As a widely used plastic material, polyethylene terephthalate (PET) is a significant source of microplastics. Osteoporosis (OP) is a prevalent systemic skeletal disorder; however, current research on the molecular mechanisms underlying the association between polyethylene terephthalate microplastics (PET-MPs) and osteoporosis remains limited. In this study, network toxicology and bioinformatics approaches were employed to explore the potential relationship and core mechanisms between PET-MPs and osteoporosis. Target genes of PET-MPs were retrieved from the PubChem and Swiss Target Prediction databases, while OP-related targets were obtained from the GeneCards, OMIM, TTD, and GEO databases, and common targets were identified through intersection analysis. A protein-protein interaction (PPI) network was constructed using the STRING database, core targets were screened using Cytoscape software, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Molecular docking verification was conducted via CB-Dock2. A total of 67 common targets were identified, and PPI network analysis revealed 9 core genes, including AKT1, SRC, and RAD51, among others. GO enrichment analysis indicated that PET-MPs affected osteoporosis primarily through processes such as cellular response to chemical stress and PI3K/Akt signal transduction. KEGG enrichment was mainly concentrated in pathways including chemical carcinogenesis–reactive oxygen species and the VEGF signaling pathway. Molecular docking results demonstrated favorable binding affinity between all core targets and PET-MPs, with RAD51 (−7.4 kcal/mol) and KDR (−7.1 kcal/mol) exhibiting the optimal binding affinity. These findings suggest that PET-MPs disrupt bone homeostasis by inducing oxidative stress, interfering with cellular functions, and impairing angiogenesis, thereby elevating the risk of osteoporosis. This study provides a theoretical basis for future studies on the skeletal toxicity mechanisms of microplastics and subsequent experimental validation.