Estrogen-receptor alpha (ERα) neurons in the ventrolateral region of the ventromedial hypothalamus (VMH_VL) control an array of sex-specific responses to maximize reproductive success. In females, these VMH_VL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERα VMH_VL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMH_VL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERα and Tac1 signaling. Disrupting the development of Nkx2-1⁺ VMH_VL neurons results in female-specific obesity, inactivity, and loss of VMH_VL neurons coexpressing ERα and Tac1. Unexpectedly, two responses controlled by ERα⁺ neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMH_VL neurons marked by ERα, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses.