Oral administration of astaxanthin (AST), a potent antioxidant, is limited owing to its low solubility, physicochemical stability, and bioavailability. This study developed pH-responsive nanocarriers by the electrostatic self-assembly of 2,2,6,6-tetramethylpiperidine-1-oxyradical (TEMPO)-oxidized cellulose nanofibers (TCNFs) and chitosan (CS) to enhance the intestinal delivery of AST. The TCNF/CS@AST nanoparticles were optimized through single-factor experiments and Box-Behnken design, subsequently overcoming the hydrophobicity of AST and demonstrating improved stability against environmental stressors and controlled release in the intestinal environment. Transmission electron microscopy confirmed the near-spherical shape of these nanoparticles, with an average hydrodynamic diameter of 64 nm. TCNF/CS@AST enhanced the antioxidant effectiveness of AST after digestion and in lipopolysaccharide-stimulated RAW 264.7 cells while demonstrating good cellular compatibility. These nanoparticles present a promising strategy for the oral delivery of hydrophobic bioactive compounds orally, with potential applications in precision nutrition.