(-)-Epicatechin and quercetin have attracted considerable attention for their potential therapeutic application in non-communicable chronic diseases. A novel hybrid inulin–soy protein nanoparticle formulation was simultaneously loaded with (-)-epicatechin and quercetin (NEQs) to improve the bioavailability of these flavonoids in the human body, and NEQs were synthesized by spray drying. After process optimization, the physicochemical and functional properties of NEQs were characterized including in vitro release, in vitro gastrointestinal digestion, and cell viability assays. Results showed that NEQs are an average size of 280.17 ± 13.42 nm and have a zeta potential of −18.267 ± 0.83 mV in the organic phase. Encapsulation efficiency of (-)-epicatechin and quercetin reached 97.04 ± 0.01 and 92.05 ± 1.95%, respectively. A 3.5% soy protein content conferred controlled release characteristics to the delivery system. Furthermore, NEQs presented inhibitory effects in Caco-2, but not in HepG-2 and HDFa cell lines. These results contribute to the design and fabrication of inulin–soy protein nanoparticles for improving the bioavailability of multiple bioactive compounds with beneficial properties.