The nervous system is constantly infiltrated by blood-derived sentinels known as perivascular macrophages. Their immediate precursors have not yet been identified in situ and the mechanism that governs their recruitment is mostly unknown. Here, we provide evidence that CD68⁺GR1⁻ monocytes can give rise to perivascular macrophages in mice suffering from endotoxemia. After adhesion to the endothelium, these monocytes start to crawl, adopt a rod-shaped morphology when passing through capillaries, and can manifest the ability to proliferate and form a long cytoplasmic protuberance. They are attracted in greater numbers during endotoxemia by a combination of vasoregulatory molecules, including TNF (tumor necrosis factor), interleukin-1β, and angiopoietin-2. After a period of several hours, some of them cross the endothelium to expand the population of perivascular macrophages. Depletion of adherent monocytes and perivascular macrophages can be achieved by injection of anti-angiopoietin-2 peptide-Fc fusion protein. This study extends our understanding of the behavior of monocytes at the blood–brain interface and provides a way to block their infiltration into the nervous tissue under inflammatory conditions.