Dietary polyphenols are potential anti-inflammatory agents, and their combinations with enhanced biological activities may lower toxicity and side effects. The objective of this work was to investigate the potential synergistic anti-inflammatory activities of apigenin and curcumin co-nanoencapsulated in sodium caseinate, with comparison to unencapsulated polyphenol combinations. Non-toxic concentrations of apigenin, curcumin, and their combinations in the free and co-encapsulated forms were studied in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Combinations of free polyphenols produced stronger inhibition of nitric oxide (NO) production, more significant at a higher proportion of curcumin, which was further enhanced after co-encapsulation. The enhanced reduction of NO was concomitant with the decreased expression of iNOS, the enhanced inhibition of pro-inflammatory cytokines of IL-6 and TNF-α, and the reduced production of intracellular reactive oxygen species. The potential multi-target effects and the enhanced solubility, proximity, and bioavailability of AP and CUR after co-encapsulation contributed to the synergistic activities. These results demonstrated that co-nanoencapsulation of apigenin and curcumin may enable the practical application utilizing the synergistic anti-inflammation effects to improve health.