Curcumin and resveratrol are natural compounds whose strong antioxidant activities are highly beneficial in the human diet. Unfortunately, their physicochemical properties result in poor stability in their chemical and antioxidant activities, which limits their utilization in food and pharmaceutical applications. In this study, liposomal nanoencapsulation was developed as a strategy to overcome these limitations and improve the antioxidant effects of these compounds. The physicochemical characteristics of co-encapsulated liposomes were evaluated and compared to formulations containing each compound individually. Liposomes co-encapsulating curcumin and resveratrol presented a lower particle size, lower polydispersity index and greater encapsulation efficiency. The formulation of liposomes co-loading curcumin and resveratrol at 5 : 1, exhibited the lowest particle size (77.50 nm), lowest polydispersity index (0.193), highest encapsulation efficiency (reaching 80.42 ± 2.12%), and strongest 2,2-diphenyl-1-picrylhydrazyl scavenging, lipid peroxidation inhibition capacity and reducing power. Additionally, liposomes loading both curcumin and resveratrol displayed a higher ability during preparation, storage, heating and surfactant shock than those loaded with individual polyphenol. Infrared spectroscopic and fluorescence techniques demonstrated that the curcumin mainly located in the hydrophobic acyl-chain region of liposomes, while the resveratrol orientated to the polar head groups. These orientations could have synergistic effects on the stabilization of liposomes. Our findings should guide the rational design of a co-delivery liposomal system regarding the location and orientation of bioactive compounds inside the lipid bilayer.