Goji berries (Lycium barbarum L.) are extremely rich in bioactive compounds, including phenolics, flavonoids, and vitamin C, which contribute to the strong antioxidant and immunomodulatory properties, positioning them as a promising candidate for nutraceutical applications. However, due to some limitations such as poor bioavailability and instability, encapsulation via spray drying with polymeric carriers provides a practical strategy to improve their stability, bioavailability, and applicability in the health sector. In this study, goji berry extract (GBE) was obtained via ultrasound-assisted extraction (UAE) and encapsulated using spray drying with four different polymers: alginate, pectin, Eudragit E100 and RS30D. GBE-loaded microparticles showed improved production yields (e.g., 40.3% for Alginate + GBE vs. 13.9% for Alginate alone) and varying particle sizes (1.9–4.4 µm). The antioxidant/antiradical activities were retained to different extents, depending on the carrier, with RS30D + GBE displaying the highest TPC (15.51 mg GAE (gallic acid equivalents)/g), FRAP (59.83 µmol FSE (ferrous sulphate equivalents)/g), and DPPH activities (3.50 mg TE (Trolox equivalents)/g). Biocompatibility was confirmed in HT29-MTX cell lines for all produced microparticles. These findings support the use of spray-dried polymeric carriers to enhance the functional performance and stability of goji berry bioactive compounds in future nutraceutical applications.