Environmental factors interact with biological and genetic factors influencing the development and well-being of an organism. The interest to better understand the role of environment on behavior and physiology led to the development of animal models of environmental manipulations. Environmental Enrichment (EE), an environmental condition that allows cognitive and sensory stimulation as well as social interaction, improves cognitive function, reduces anxiety and depressive-like behavior, and promotes neuroplasticity. In addition, it exerts protection against neurodegenerative disorders, cognitive aging and deficits aggravated by stressful experiences. Given the beneficial effects of EE on brain and behavior, preclinical studies focus on its protective role as an alternative, non-invasive manipulation, to help an organism to cope better with stress. A valid, reliable and effective animal model of chronic stress that enhances anxiety and depression-like behavior is the Chronic Unpredictable Mild Stress (CUMS). The variety of stressors and the unpredictability in the time and sequence of exposure to prevent habituation, render CUMS an ethologically relevant model. CUMS has been associated with dysregulation of the Hypothalamic-Pituitary-Adrenal axis, elevation in the basal levels of stress hormones, reduction in brain volume, dendritic atrophy and alterations in markers of synaptic plasticity. Although numerous studies have underlined the compensatory role of EE against the negative effects of various chronic stress regimens (e.g., restraint, social isolation), research concerning the interaction between EE and CUMS is sparse. The purpose of the current systematic review is to present up-to-date research findings regarding the protective role of EE against the negative effects of CUMS.