The nervous and immune systems are closely related1. Although psychological stress is known to modulate immune function, the mechanistic pathways linking brain stress networks to peripheral leukocytes remain poorly understood2. Here, we show that different brain regions shape the distribution and function of leukocytes throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we show that motor circuits induce rapid mobilization of neutrophils from bone marrow to peripheral tissues by chemokines that attract neutrophils derived from skeletal muscle. In contrast, the paraventricular hypothalamus controls the emission of monocytes and lymphocytes from secondary lymphoid organs and blood into the bone marrow by direct signaling of intrinsic glucocorticoids to cells. These stress-induced, counterdirectional, and population-wide changes in leukocytes are associated with impaired susceptibility to the disease. On the one hand, acute stress modifies innate immunity by reprogramming neutrophils and directing their recruitment to injury sites. On the other hand, neurocyte changes mediated by corticotropin-releasing hormone (CRH) neurons protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that different brain regions adapt to the leukocyte landscape differently and rapidly during psychological stress, thus calibrating the immune system’s ability to respond to physical threats.