Natural hydrophobic antioxidants (e.g., β-carotene and naringenin) are severely limited in their application due to their low solubility and high sensitivity properties. In this study, cationic lipid-assisted nanoparticles loaded with β-carotene (NP-BC) and naringenin (NP-NAR), respectively, were fabricated and characterized, and their digestive and metabolic behaviors were evaluated using static digestion models and in vivo imaging. The particle size and potential of cationic polymer nanoparticles changed during digestion but retained their structural integrity, which was conducive to targeted drug delivery to the liver and prolonged the in vivo circulation of the drug. It is noteworthy that whereas NP-BC was more advantageous in lowering hepatic fat deposition, NP-NAR successfully limited weight gain. This study proved that cationic polymer nanoparticles are promising carriers for transporting natural hydrophobic antioxidants and may be beneficial for improving nutrition absorption and targeted delivery to alleviate metabolic dysfunction-associated steatotic liver disease (MASLD) symptoms.