Background: Radiotherapy is a common treatment for brain tumors, yet it often leads to cognitive decline. Past understanding suggested this damage was irreversible due to DNA damage and cell death. However, recent studies propose that it may be reversible, as it affects active cells. Scientists focus on hippocampal activity, crucial for learning and memory, to explore this. Radiation is thought to decrease neurogenesis and increase neuroinflammation in the hippocampus. Anti-inflammatory drugs are suggested as a potential solution to mitigate cognitive decline from radiation.Aims: Analyzing the effects of radiotherapy in combination with cannabidiol (CBD) medication on neuronal function and synaptic plasticity in the hippocampus.Methods: Adult mice are given cannabidiol daily for 4 weeks. After 2 weeks, they undergo part-brain-radiotherapy (PBRT) to one hemisphere. Brain-tissue is then harvested for long-term potentiation (LTP) recordings, spine density/morphology analysis, and microglia polarization assessment.Results: PBRT inhibited LTP in the irradiated hemisphere, while the non-irradiated hemisphere remained unaffected. Pre-treatment with CBD rescued LTP. Additionally, irradiated hemispheres showed reduced dendritic spine density, a phenomenon mitigated by CBD administration. Furthermore, irradiated hemispheres without CBD exhibited increased pro-inflammatory (M1) microglia expression, whereas CBD-treated groups displayed elevated anti-inflammatory (M2) microglia expression in the irradiated hemisphere compared to the non-irradiated hemisphere.Conclusion: In this investigation, we hypothesize that the inhibition of LTP following PBRT is linked to heightened neuroinflammation and reduced spine density. The application of CBD exhibits promising effects in mitigating these detrimental consequences. Nevertheless, the precise molecular mechanism underlying CBD's action warrants elucidation and necessitates further exploration.