Soy isoflavones (SIF) are soybean phytochemicals that are considered to be biologically active components that protect from neurodegenerative diseases. In this study, the therapeutic effect of SIF was evaluated in a diabetic Goto-Kakizaki (GK) rat model. Twenty male GK rats were randomly divided into diabetes mellitus (DM) model group and SIF+DM group (n=10 in each group). Twenty age-matched male Wistar rats were randomly divided into control group (CON group) and CON+SIF group, with 10 rats in each group. The learning and memory functions of the animals were determined by the Morris water maze (MWM) test. Hematoxylin-eosin staining (HE) was performed to examine pyramidal neuron loss in the CA1 area of the hippocampus. Markers of oxidative stress (OS) were measured to evaluate oxidative stress-mediated injury. RT-PCR and western blotting were used to analyze the expression of nuclear factorerythroid2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone1 (NQO1). Treatment with SIF for 4 weeks alleviated the cognitive dysfunction of the GK rats as determined by the MWM test. Moreover, SIF treatment also reduced diabetes-related oxidative reactions. In addition, SIF enhanced the expression of Nrf2, HO-1 and NQO1, suggesting a potential antioxidation mechanism for the effect of SIF. These findings suggest that SIF can be considered candidates for inhibiting the progression of diabetes-induced cognitive dysfunction, provide novel insights into the antioxidant effect of SIF and further strengthen the link between oxidative stress and diabetes.