Cellular senescence is the results of aging and age-related diseases, and the development of anti-aging methods may improve health and extend longevity. The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo, but has poor water solubility and limited bioavailability. In this study, a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides (WPI-GOS) Maillard conjugate, which could recognize senescence associated β-galactosidase in senescent cells. The fisetin nanoparticles possessed a high encapsulation efficiency, excellent dispersibility in water, good storage stability and well biocompatibility. Moreover, they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy, and inhibit the oxidative stress-induced cellular senescence in vitro. Thus, this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.