Chitosan (CS) and its water-soluble derivatives—hydroxypropyl chitosan (HPCS), quaternary ammonium salt of chitosan (HACC), and carboxymethyl chitosan (CMCS)—were evaluated for their antioxidant activity through in vitro and in vivo experiments. The results showed that all derivatives exhibited scavenging abilities against DPPH, superoxide, and hydroxyl radicals, as well as reducing power. HPCS and HACC showed significantly higher scavenging activity compared to CS, with HPCS showing the strongest effect. The antioxidant activity of the four samples followed the order HPCS > HACC > CMCS > CS, and increased with concentration. In vivo, oral administration of CS and its derivatives reduced lipid peroxides (LPO) and free fatty acids (FFA) in serum while increasing superoxide dismutase (SOD) activity. HPCS and HACC significantly reduced LPO, FFA, and increased SOD compared to the high-fat control group (p < 0.05). These findings suggest that CS and its derivatives have good antioxidant properties, with activity influenced by molecular structure. The study highlights the potential of CS derivatives as natural antioxidants for preventing oxidative stress and hyperlipidemia.Chitosan (CS) and its water-soluble derivatives—hydroxypropyl chitosan (HPCS), quaternary ammonium salt of chitosan (HACC), and carboxymethyl chitosan (CMCS)—were evaluated for their antioxidant activity through in vitro and in vivo experiments. The results showed that all derivatives exhibited scavenging abilities against DPPH, superoxide, and hydroxyl radicals, as well as reducing power. HPCS and HACC showed significantly higher scavenging activity compared to CS, with HPCS showing the strongest effect. The antioxidant activity of the four samples followed the order HPCS > HACC > CMCS > CS, and increased with concentration. In vivo, oral administration of CS and its derivatives reduced lipid peroxides (LPO) and free fatty acids (FFA) in serum while increasing superoxide dismutase (SOD) activity. HPCS and HACC significantly reduced LPO, FFA, and increased SOD compared to the high-fat control group (p < 0.05). These findings suggest that CS and its derivatives have good antioxidant properties, with activity influenced by molecular structure. The study highlights the potential of CS derivatives as natural antioxidants for preventing oxidative stress and hyperlipidemia.