Protein therapeutics offer excellent potential for disease treatments, but are constrained by rapid systemic clearance. Fibroblast growth factor 21 (FGF21), a promising neuroprotective therapeutic candidate, is hindered from further clinical application due to its short half-life. Inspired by the in vivo protein/zinc complexation, we identified a strong interaction between FGF21 and zinc, forming an FGF21/zinc complex through non-covalent interactions. A stable nanocomplex (FGF21/Zinc NC) was further optimized using polyvinylpyrrolidone (PVP) for steric stabilization, which was selected through molecular docking and stability assays. FGF21/Zinc NC demonstrated enhanced pharmacokinetics, with about 3-fold prolonged systemic retention and over 3-fold accumulation in the brain compared to free FGF21. Both in vitro and in vivo, FGF21/Zinc NC outperformed free FGF21, significantly alleviated oxidative stress in neuronal cells, suppressed neuroinflammation to attenuate microglial and astrocyte overactivation, reduced infarct volume by 45%, and accelerated motor recovery in a stroke mouse model. This innovative approach provides a facile and effective strategy to enhance the stability and therapeutic potential of protein-based drugs.