Objective To investigate the effect of propofol on cognitive function in young obese rats, and to explore its relationship with heme oxygenase 1 (HO-1), superoxide dismutase 1 (SOD1) protein expression and plasma S100 calcium-binding protein β (S100β) expression. Methods A total of 140 male SD rats aged 21 days were randomly divided into normal diet group (n=40) and high-fat diet group (n=100), and the rats were fed with a normal diet and a high-fat diet, respectively. After 4 weeks of feeding, 40 rats of the high-fat diet group with body mass ≥ the average body mass+1.4 times of the standard deviation of the normal diet group were designated as obese rats. The rats in the normal diet group were randomly divided into the normal lipid emulsion solvent group (NL group) and the normal propofol group (NP group), and the 40 obese rats were randomly divided into the obese lipid emulsion solvent group (OL group) and the obese propofol group (OP group), with 20 rats in each group. The rats in the propofol groups were intraperitoneally given propofol 100 mg/kg, and those in the lipid emulsion solvent groups (control groups) were intraperitoneally given lipid emulsion solvent 100 mg/kg, once a day for 7 days. On the first day after drug withdrawal, Morris water maze test was performed to evaluate the spatial learning and memory abilities of rats in each group. Meanwhile, the plasma S100β protein content of each group was detected by enzyme-linked immunosorbent assay, the expression levels of HO-1 and SOD1 protein in hippocampus were detected by Western blotting, and the changes of neurons in hippocampus CA1 area were observed by hematoxylin-eosin staining. Results Compared with the OL group, the escape latency time was significantly prolonged on 1-5 days (all P<0.05), the third quadrant residence time was significantly shortened (P<0.05), the times of crossing platform was significantly decreased (P<0.05), the expression of plasma S100β protein was significantly increased (P<0.05), the relative expression levels of HO-1 and SOD1 protein in hippocampus were significantly decreased (both P<0.05), and the number of neurons in hippocampal CA1 area was significantly decreased (P<0.01) in the OP group. Compared with the NL group, the escape latency time of the NP group was significantly prolonged on 1-2 days (both P<0.05), and there were no significant differences in other indexes mentioned above (all P>0.05). Conclusion Propofol can down-regulate the expression of anti-oxidant factors HO-1 and SOD1 in the hippocampus of young obese rats, leading to increase of S100β expression and oxidative stress and eventually causing cognitive impairment.