Depression is very common brain disorder having characteristics like mood swings, anxiety, insomnia, cognitive impairment with suicidal tendency. Fluoxetine is a precursor of selective serotonin reuptake Inhibitors (SSRIs) which is very popular member of this category used for the treatment of this disorder. Vitamin-D generally requires for normal growth of bone. The exact biological mechanisms linking to Vitamin-D and depression are not fully understood but some studies reported that it has some biological activity in neurological development and function. This research was carried out to investigate the neuroprotective effects of VitaminD. We used chronic unpredictable mild stress (CUMS) animal model for depression where animals are constantly exposed to a sequence of unpredictable mild stressors which trigger number of life stress events. Undoubtedly there are so many characteristic symptoms and neurological deformity observes in CUMS-induced animals which are identical to those found in human depressed patients. Depression like behaviors were recorded as open-field test (locomotor activity), force swim test (immobility time), tail suspension test (immobility time), splash test (grooming time) in rats. Brain homogenate was used to estimate oxidative stress (glutathione-GSH, superoxide dismutase-SOD, lipid peroxidation-TBARS, catalase, nitrite oxide and total protein). CUMS induced rats displayed depression like behaviors, cognitive impairment and various biochemical changes in brain. However, treatment with the combination of Fluoxetine and Vitamin-D significantly restored the depression like behaviors and biochemical impairments in rats. Vitamin-D in combination of fluoxet