Cannabidiol (CBD), a non-psychotomimetic cannabinoid from the plant Cannabis sativa, has been reported as a potential candidate for the treatment of cocaine use disorders in humans. However, the underlying mechanisms mediating these effects remain largely unknown. Prior work from our laboratory has shown that in Uruguay, street-seized cocaine samples were frequently adulterated with caffeine. We have shown that the presence of caffeine acts as an enhancing agent in the induction of cocaine-induced locomotor sensitization. Administration of CBD completely blocked this behavioral effect. Expression of this behavior was associated with neuroinflammatory processes. We thus hypothesized that the anti-inflammatory properties of CBD could prevent the drug-induced neuroinflammatory process, halting the neural-glial adaptation thought to be responsible for the locomotor sensitization. Male adult mice were treated with CBD and CocCaf or its respective vehicles, for 5 days. Locomotor activity was automatically recorded and quantified in an open field by the video-tracking software EthoVision XT 17.0. In the current work we report that administration of cocaine and caffeine combined resulted in locomotor sensitization and that this behavioral effect was attenuated by the presence of CBD. Histological analysis of reward related structure Nucleus Accumbens revealed that animals exposed to the drugs combination had developed neuroinflammatory processes in this area, as measured by increased microglial activation (Iba-1 immunoreactivity). Modulation by CBD of the drug-induced neuroinflammatory processes might be involved in the attenuation of the behavioral response to repeated exposure to cocaine and caffeine combination that we report here.