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Platelet-derived growth factor-BB (PDGF-BB), a core functional isoform of the PDGF family, serves as a central regulator of cell proliferation, migration, differentiation, and tissue remodeling. Extensive preclinical and clinical evidence indicates that PDGF-BB expression exhibits profound spatiotemporal heterogeneity during natural aging and across various pathological conditions, including cardiovascular, neurodegenerative, and musculoskeletal diseases, as well as malignancies. Importantly, these dynamic expression patterns are intrinsically linked to disease progression and distinct aging phenotypes. Mechanistically, PDGF-BB initiates complex intracellular signaling cascades-such as the ERK, JNK, PI3K-AKT, and mTOR pathways-via specific engagement with PDGFRα/β dimers. Through these networks, PDGF-BB orchestrates intercellular communication and maintains microenvironmental homeostasis in a highly dose-dependent and cell-type-specific manner. Consequently, pharmacological interventions using small molecules, natural products, and biological agents have demonstrated efficacy in modulating PDGF-BB expression and its downstream signaling, presenting promising therapeutic targets for aging-related disorders and associated tissue damage. This review systematically synthesizes the heterogeneous expression profiles of PDGF-BB across natural aging and diverse disease contexts. We delineate the molecular mechanisms underlying its role in driving senescence and pathological progression, and critically evaluate the translational potential and current limitations of PDGF-BB-targeted therapies. By comprehensively mapping the biological network of PDGF-BB, this review aims to provide a conceptual framework for future basic research and clinical translation.