Chronic gut inflammation is associated with neuroinflammation and brain diseases. Yet, the regional pattern and single-cell resolution of the brain immune response to chronic gut inflammation remains elusive. Combining confocal microscopy and multiomic analyses, we observed that chronic colitis-derived systemic inflammation results in a midbrain-specific inflammatory response characterized by an inflammatory shift of microglial clusters, CD8+ T cell extravasation, and increased numbers of vessel-associated neutrophil granulocytes. Myeloid cell targeting after colitis onset resulted in a 67% reduction of midbrain microglia and prevented dopaminergic neuron loss in the substantia nigra pars compacta. Collectively, we provide the first single-cell resolution of an innate and adaptive immune response to chronic gut inflammation in the midbrain and identified a detrimental role of myeloid cells in midbrain dopaminergic neuron loss. These results substantially advance the understanding of the gut-immune-brain axis that links peripheral inflammation to distinct neuroinflammatory and neurodegenerative processes related to Parkinson’s disease.