Caffeic acid phenethyl ester (CAPE), a polyphenol from propolis, is well recognized for its anti-inflammatory, antioxidant, antimicrobial, and osteogenic properties. This study aimed to develop macroporous bone scaffolds composed of a chitosan/agarose matrix reinforced with nanohydroxyapatite and enriched with stable CAPE derivatives to enhance their biomedical potential for applications in bone tissue engineering and regenerative medicine. A comprehensive evaluation of microstructural and biological properties of the produced scaffolds was conducted. The fabricated scaffolds exhibited high porosity (49–60%) with interconnected pores and compressive strength (1.2–1.8 MPa), closely resembling cancellous bone and indicating suitability for bone regeneration. They were biocompatible, promoted osteoblast adhesion, proliferation, and differentiation, and supported apatite deposition on their surfaces, demonstrating strong bioactivity and potential for implant osseointegration. Importantly, the scaffolds did not trigger excessive production of reactive oxygen or nitrogen species, suggesting a low risk of inflammatory responses. Additionally, CAPE-enriched scaffolds inhibited biofilm formation by Staphylococcus aureus and Staphylococcus epidermidis, reducing the risk of implant-associated infections. In summary, these CAPE-modified scaffolds integrate optimal microstructural and biological features, such as reducing oxidative stress and inhibiting biofilm formation, and thus offer a promising strategy for enhancing bone repair and regeneration in clinical applications.