In the present research, an orange extract (OE) was obtained and encapsulated in a zein matrix for its subsequent physicochemical characterization and evaluation of its antioxidant capacity. The OE consists of phenolic compounds and flavonoids extracted from orange peel ( Citrus sinensis) by ultrasound-assisted extraction (UAE). The results obtained by dynamic light scattering (DLS) and scanning electron microscopy (SEM) indicated that zein nanoparticles with orange extract (NpZOE) presented a nanometric size and spherical shape, presenting a hydrodynamic diameter of 159.26 ± 5.96 nm. Furthermore, ζ-potential evolution and Fourier transform infrared spectroscopy (FTIR) techniques were used to evaluate the interaction between zein and OE. Regarding antioxidant activity, ABTS and DPPH assays indicated no significant differences at high concentrations of orange peel extract and NpZOE; however, NpZOE was more effective at low concentrations. Although this indicates that ultrasonication as an extraction method effectively obtains the phenolic compounds present in orange peels, the nanoprecipitation method under the conditions used allowed us to obtain particles in the nanometric range with positive ζ-potential. On the other hand, the antioxidant capacity analysis indicated a high antioxidant capacity of both OE and the NpZOE. This study presents the possibility of obtaining orange extracts by ultrasound and coupling them to zein-based nanoparticulate systems to be applied as biomedical materials functionalized with antioxidant substances of pharmaceutical utility.