Abstract: To investigate the protective effects and potential mechanisms of safflower petal polysaccharides on D-galactose-induced brain tissue damage in aging mice, KM mice were randomly divided into a normal control group, a model group, a positive control group, and low-, medium-, and high-dose safflower petal polysaccharide groups (100, 200 and 400 mg/kg/d), with 10 mice in each group. Modeling and drug administration were conducted simultaneously for 8 weeks. After the experiment, body weight and organ indices were analyzed, Nissl staining was used to examine hippocampal tissue changes, and the levels of AChE and T-NOS in brain tissue were compared. Western blot was employed to detect the expression of apoptosis-related proteins, including P53, Bax, and caspase-3. Additionally, metabolomics analysis was performed to assess changes in brain tissue metabolites. The results showed that safflower petal polysaccharides had minimal effects on body weight and organ indices. Compared with the normal group, the model group exhibited a reduction in Nissl bodies, along with significant increases in AChE and T-NOS enzyme activities by 58.22% and 17.56%, respectively (P<0.01). The protein expression of P53, Bax, and Caspase-3 was upregulated by 48.41%, 25.08%, and 37.91%, respectively (P<0.05). In contrast, the polysaccharide-treated groups showed an increase in Nissl bodies, a significant decrease in AChE activity, and reduced T-NOS activity in the medium- and high-dose groups (P<0.01). The expression of P53, Bax, and Caspase-3 proteins was also downregulated, particularly in the high-dose safflower petal polysaccharide group, which exhibited significant reductions of 37.88%, 37.12% and 30.02%, respectively (P<0.05). Metabolomic pathway enrichment analysis revealed that safflower petal polysaccharides primarily regulated arginine biosynthesis and glutathione metabolism pathways. In conclusion, safflower petal polysaccharides effectively alleviated D-galactose-induced brain tissue damage in mice. The underlying mechanism may involve the modulation of P53, Bax, and Caspase-3 protein expression, as well as the regulation of arginine biosynthesis and glutathione metabolism pathways. These findings provide a theoretical basis for expanding the application of safflower petal resources in anti-aging research.