The borders of the central nervous system (CNS) host a repertoire of immune cells and mediate critical neuroimmune interactions, including the infiltration of peripheral myeloid cells into the CNS. Despite the fundamental role of leukocyte infiltration under physiological and pathological conditions, the neuroanatomical route of cell entry into the brain remains unclear. Here, we describe a specialized structure underneath the hippocampus, the velum interpositum (VI), that serves as a site for myeloid cell entry into the CNS. The VI functions as an extra-parenchymal leptomeningeal extension containing distinct myeloid cells subsets. Fate-mapping studies confirm meningeal and peripheral myeloid cell occupancy within the VI. Additionally, we highlight the distinct use of this route in the developing, irradiated, and demyelinating disease brain, indicating that myeloid cell trafficking through the VI could have important clinical implications for neurological disease.