Lead-induced oxidative stress was generated in mice under lead exposure, and the antioxidant activity of chitosan (CS) and its water-soluble derivatives was compared in vivo. The results indicated that there was significant difference (P<0.05) for the biochemical variables of lead-treated groups. After lead exposure, the contents of reduced glutathione (GSH) and total thiols (T-SH) in blood and tissues decreased, and the contents of protein oxidation, oxidized glutathione (GSSG), malondialdehyde (MDA) and reactive oxygen species (ROS) increased compared with the control group. Administration of CS and its derivatives made for the removal of lead from blood and tissues, especially for hydroxypropyl chitosan (HPCS) and quaternary ammonium salt of chitosan (HACC). And the changed biochemical variables showed recovery with different degrees, which indicated that CS and its derivatives were helpful for alleviating lead-induced oxidation damage in vivo. But the antioxidant activity for different CS was different, followed by HPCS>HACC>carboxymethyl chitosan (CMCS)>CS, which was in close with the introduction of different substituent groups. In particular, for the dietary of HPCS, there was significant recovery for the changed biochemical variables (P<0.05) in mice after lead exposure, except GSSG in kidney and MDA in brain.