Bone regeneration is a complex physiological process involving multiple signaling pathways, such as oxidative stress, inflammation, and cellular differentiation. Phenolic compounds have emerged as promising bioactive agents due to their antioxidant, anti-inflammatory, and osteogenic properties. This chapter is focused on describing molecular mechanisms by which phenolic compounds regulate bone regeneration, including the modulation of the nuclear factor kappa-B (NF-κB) and Nrf2 pathways. A short overview of chemical characteristics and biological activities of multiple subclasses of phenolic compounds is provided. The discussion extends to the integration of polyphenols into biomaterials-based applications, such as metal-phenolic networks (MPNs) and bioactive scaffolds, highlighting significant potential of these molecules in enhancing bone regeneration. Several challenges related to bioavailability and clinical translation have been identified, along with the recent advancements in the improvement of drug-like properties of phenolic compounds. Future research should focus on optimizing the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of phenolic agents and understanding the molecular bases of their biological activities to develop innovative biomaterial-based strategies for bone tissue engineering and regenerative medicine.