Peels of Washington Navel (WAS), Navelina (NAV), and Vaniglia Apireno (VAN) orange fruits from Ribera (Sicily, Italy) represent abundant by-products of the Italian agro-food sector. In this work, volatile (VE) and non-volatile (NVE) extracts were obtained from fresh peels using a microwave-assisted protocol, and were characterized for their content in secondary metabolites and bioactivity. VEs exerted antibacterial activity against different pathogens, and were toxic on Caco2 cells. Their main component was limonene (>85 %). NVEs inhibited tyrosinase, amylase, and glucosidase in vitro, and exerted significant antioxidant effects on THP-1 XBlue cells. They showed also anti-inflammatory properties, by decreasing NF-κB activity in LPS-stimulated cells. Putative molecular effectors were highlighted by multivariate correlation analysis. Overall, NVEs may represent novel sustainable nutraceutical ingredients with anti-inflammatory and metabolic properties, and can be obtained by using eco-sustainable approaches. Our results will encourage the reuse of by-products of the orange processing chain and will contribute to increase its circularity in the future.