Advances in the early detection and treatment of breast cancer has greatly improved survival, but chemotherapy is often associated with lingering neurological side-effects commonly referred to as “chemo-fog”. Despite the high incidence and significant impact of chemotherapy-induced neurological symptoms on the quality of life of breast cancer survivors, little is known about the physiological mechanisms underlying the development of cognitive and affective deficits. Our hypothesis is that chemotherapy-induced hypothalamic-pituitary-adrenal (HPA) axis activation and neuroinflammation contribute to the observed behavioral changes. Within hours of administering doxorubicin + cyclophosphamide to mice, there is a significant increase in serum corticosterone and proinflammatory cytokine concentrations, as well as increased proinflammatory cytokine expression in various brain regions, including the hippocampus, cortex and hypothalamus. Cognitive and affective deficits, as measured using the Barnes maze, novel object recognition task, elevated plus maze, and forced swim test, emerge within three days of the first chemotherapy treatment. In addition, chemotherapy treatment is associated with a significant decrease in dendritic spine density within the CA1 and CA3 regions of the hippocampus. The administration of minocycline prevents the chemotherapy-induced neuroinflammation and behavioral deficits without altering circulating corticosteroid concentrations. In contrast, exposure to stress prior to chemotherapy administration significantly increases the neuroinflammatory and depressive-like effects. In sum, these data suggest that the administration of doxorubicin and cyclophosphamide in doses that approximate the typical dose used for women being treated for breast cancer, results in HPA axis activation, neuroinflammation, alterations in dendritic spine density, and concomitant affective and cognitive deficits in female mice. The effects of chemotherapy on neuroinflammation and behavior are further amplified by prior exposure to stress. Together, these data suggest that stress exposure could be an important factor in determining an individual’s susceptibility to the neurobehavioral side-effects of chemotherapy. Supported by a Pelotonia Idea Award to ACD and MBL.