More than half of long-term brain tumor survivors develop irreversible cognitive decline that severely affect their quality of life. However, there is no pre-clinical model that allows long-term assessment of cognition, and there is no treatment which ameliorates cognitive deficits in patients. Here, we report a novel glioma mouse model that offers manageable tumor growth and reliable assessment of cognitive functions in a post-treatment manner. Using this model, we found that fractionated whole-brain irradiation (fWBI), but not tumor growth, results in memory deficits. Transient inhibition of CSF-1R during fWBI prolongs survival of glioma-bearing mice and fully prevents fWBI-induced memory deficits. This result suggests that CSF-1R inhibition during radiotherapy can be explored as an approach to improve both survival and cognitive outcomes in patients who will receive fWBI. Taken together, the current study provides a proof of concept of a powerful tool to study radiation-induced cognitive deficits in glioma-bearing animals.