Electrospun nanocomposite fibers have emerged as promising scaffold materials in tissue engineering due to their high surface area, tunable porosity, and structural resemblance to the native extracellular matrix. However, their limited surface functionality and poor bioactivity often restrict effective cell–material interactions, posing challenges for successful tissue integration and regeneration. In this study, cerium oxide (CeO₂) nanoparticles were incorporated into polyvinylidene fluoride (PVDF) nanocomposite fibers to enhance their mechanical and interfacial properties for scaffold-based biomedical applications. CeO₂, known for its antioxidant, anti-inflammatory, and regenerative characteristics, was embedded into the PVDF matrix via electrospinning. The inclusion of CeO₂ led to a significant increase in surface roughness, Young’s modulus, and surface energy key features that positively influence cell adhesion, spreading, and proliferation. Additionally, uniform nanoparticle dispersion within the PVDF matrix ensured consistent fiber morphology and improved mechanical stability. The engineered nanofibers demonstrate a synergistic combination of enhanced mechanical integrity and surface bioactivity, directly addressing limitations associated with conventional polymer scaffolds. These improvements suggest that CeO₂-functionalized PVDF nanocomposite fibers represent a viable approach for developing advanced tissue engineering scaffolds. This work contributes to the advancement of functional biomaterials designed to support favorable cellular responses and improve therapeutic outcomes in regenerative medicine and tissue repair.