Major Depressive Disorder (MDD) is a prevalent, persistent and severe psychiatric condition characterized by persistent feelings of depression, anhedonia, and occasional suicidal thoughts, with stress identified as a major trigger. Previous research from our lab has shown changes in mouse emotional and cognitive behavior, and cellular and molecular alterations in some brain areas such as hippocampus, striatum and prefrontal cortex. Nevertheless, the mechanism underlying depression remain elusive, and so, an effective treatment. To tackle this issue, cannabidiol (CBD) treatment has emerged as a promising novel therapeutic strategy.Therefore, we established a chronic unpredictable mild stress (CUMS) mouse model to assess the potential behavioral positive effects by low CBD (1 mg/kg) chronic treatment in the MDD-like phenotype mice by monitoring mouse performance in the open field test, novel object recognition test, tail suspension test, forced swimmin test, and Y-maze test.Our results show that a low CBD dose mitigates stress-induced behavioral despair and anxiety. We have also performed a broad morphologic and biochemical characterization, which includes a gross anatomy evaluation of different brain regions, an examination of the state and morphology of striatal medium spiny neurons, a structural synaptic plasticity analysis and a Mass Spectrometry study in both, the medial prefrontal cortex and the striatum, to have a wide view of the molecular profiles associated to the CBD treatment in the context of chronic stress. In smmary, these findings expand our comprehension of the altered pathways in MDD associated to chronic stress, facilitating potential progress in therapeutic approaches.