AbstractSoybean isoflavone (SIF) has been demonstrated to have neuroprotective effects induced by β‐amyloid peptides (Aβ) through suppressing oxidative stress; however, the explicit mechanisms still remain uncovered. In the present study, 32 Wistar rats were randomly divided into four groups: an Aβ1‐42‐treated group, a SIF + Aβ1‐42 group, a SIF‐treated group and a control group. We measured the protein content of 8‐hydroxydeoxyguanosine (8‐OhdG) and mRNA expression of 8‐oxoguanine DNA glycosylase (OGG1). The protein expression of OGG1, Bcl‐xl, Bad, beta subunit of ATP synthase (ATPB) and pyruvate dehydrogenase (PDH) in brain was also measured. The results showed that the level of 8‐OHdG in both SIF groups was significantly decreased compared to the Aβ1‐42‐treated group (p < 0.05), while the mRNA and protein expression of OGG1 in the SIF + Aβ1‐42 groups were up‐regulated compared with the Aβ1‐42‐treated groups (p < 0.05). The expression of Bcl‐xl was up‐regulated in the SIF‐treated group compared with the Aβ1‐42‐treated groups (p < 0.05), while the expression of Bad was down‐regulated in the two SIF‐treated groups (p < 0.05). Aβ1‐42 significantly down‐regulated the expression of ATPase and PDH proteins compared with the control group (p < 0.05). SIF reversed the down‐regulation effects on the mitochondrial energy metabolic enzymes induced by Aβ1‐42 (p < 0.05) in the rats. These results suggest that SIF alleviate the oxidative stress in neurons and mitochondria of rat brains mediated by Aβ1‐42, and these protective effects might be associated with the regulation of OGG1, Bad, Bcl‐xl, ATPB and PDH.