A lot of complications associated with type 2 diabetes mellitus (T2DM) are closely linked with the generation of reactive species or free radicals leading to oxidative/nitrosative stress. The aim of this study was to investigate the effect of combined administration of metformin with propionate on the degree of oxidative/nitrosative damage in the brain of rats with an experimental model of T2DM. Male Wistar rats were divided into control (healthy rats); rats with T2DM and no further therapy; rats with T2DM that received the following: metformin or propionate or propionate + metformin. Ventromedial hypothalamus samples were analyzed by transmission electron microscopy, gas-liquid chromatography, Western blotting, RT-PCR and electron paramagnetic resonance. Combined treatment resulted in normalization of neuronal NOS levels, reduction of mRNA level of induced NOS and superoxide radicals compared to untreated T2DM rats. Were also observed a decrease in the level of 8-oxyguanine and normalization of fatty acids distribution. Ultrastructural alterations of mitochondria due to oxidative/nitrosative damage of neurons` mitochondria in T2DM were partially rescued by the combined treatment. Thus, we demonstrated a positive effect of the combined use of metformin and propionate on all indicators of oxidative/nitrosative stress in T2DM.