Bone defects pose significant clinical challenges, necessitating the development of innovative strategies to effectively restore damaged bone and recover normal function. Mesenchymal stem cells (MSCs) have emerged as a promising tool for bone regeneration due to their accessibility from various sources, ease of isolation and expansion, and intrinsic ability to differentiate into osteogenic lineages with minimal ethical concerns. However, successful bone repair using MSCs requires the incorporation of biocompatible osteoinductive agents, preferably derived from natural sources. Natural polyphenols, particularly flavonoids, exhibit potent pharmaceutical properties that modulate MSC fate toward osteogenic differentiation. These secondary metabolites promote osteogenesis by interacting with key bone regulatory signaling pathways, including bone morphogenetic protein 2 (BMP2)/SMAD, wingless-related integration site (Wnt)/β-catenin, nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB), and mitogen-activated protein kinase (MAPK). Beyond their osteoinductive capacity, flavonoids possess anti-inflammatory, antibacterial, and pro-angiogenic effects, which synergistically enhance bone formation both in vitro and in vivo, thereby amplifying their therapeutic potential. This review synthesizes current insights into the interaction between MSCs and natural flavonoids, detailing the molecular mechanisms driving their synergistic effects. It also highlights recent advancements in nanoformulation-based delivery systems aimed at addressing challenges like poor solubility and bioavailability. Although preclinical data strongly support the bone-protective properties of these agents, their clinical translation remains forthcoming. Future studies must focus on optimizing delivery methods, ensuring long-term safety, and rigorously validating therapeutic efficacy across various bone disorders.

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