Major depressive disorder (MDD) is a great challenge for psychiatry with up to 40% of treatment-resistant patients. Therefore, non-pharmacological interventions such as different diets seem a promising tool. Ketogenic diet (KD) is a powerful tool for epilepsy and metabolic diseases while new clinical and animal studies show also its potential against mental disorders such as MDD, bipolar disorders and schizophrenia. Several neurobiological pathways have been suggested to mediate effect of KD for the brain and mental health with neurotrophic and neuroplasticity factor BDNF among them. Therefore, here we estimate the effect of KD in male and female C56Bl/6J and BDNF heterozygous mice under the chronic restrain model of depression. Mice were kept on medium-chain fat-based KD (paste, 75% fats, 10% proteins, 3% carbohydrates) or regular chow (RC, crushed into powder, 5% fats, 19% protein, 59% carbohydrates) during 4 weeks –2 weeks before the restrain and then 2 weeks along with daily 2-hour restrain stress. Mice were then tested in sucrose preference test (SPT), tail suspension test (TST), elevated plus maze (EPM), light-dark box (LDB), open field test (OFT), social interaction test (SIT). Postmortem blood and brain samples were taken for ex vivo studies.Stress increased anxiety in OFT (total distance, time in periphery) but not in EPM and LDB. BDNF +/- males and females were less anxious in OFT and EPM while KD increased anxiety in males in OFT and LDB. Depression-like behavior in the SPT and TST, social exploration in SIT remained unaffected by stress, diet and BDNF deficiency.