Accumulation of heavy metals (Mn and Ni) and prolonged exposure to stress are associated with adverse health outcomes. Various studies have elucidated individually the impacts of stress and metal exposures on brain constituents and function. However, no study has examined the effects of co-exposure to stress, Mn, and Ni in the brain. This study addresses this gap by evaluating oxidative and glial responses, apoptotic activity, as well as cognitive processes in a rat model. Adult Wistar rats were exposed to vehicle (control), restraint stress, 25mg/kg of manganese (Mn) or nickel (Ni), and combined restraint stress plus Mn or Ni. Following treatment, rats were subjected to several behavioral paradigms to assess cognitive function. Enzyme activity, as well as ATPase levels, were evaluated. Thereafter, an immunohistochemical procedure was utilized to evaluate neurochemical markers of glial function, myelination, oxidative stress, and apoptosis in the hippocampus, prefrontal cortex (PFC), and striatum. Results showed that stress and metal exposure increased oxidative stress markers and reduced antioxidant levels. Further, stress and metal exposure reduced various forms of learning and memory ability in rats. In addition, there were alterations in Iba1 activity and Nrf2 levels, reduced Olig2 and myelin basic protein (MBP) levels, and increased caspase-3 expression. These neurotoxic outcomes were mostly exacerbated by co-exposure to stress and metals. Overall, our findings establish that stress and metal exposures impaired cognitive performance, induced oxidative stress, and apoptosis, and resulted in demyelination, which may be worsened by combined stress and metal exposure.