Sufficient feeding is essential for animals' survival, which requires a cognitive capability to facilitate food seeking, but the neurobiological processes regulating food seeking are not fully understood. Here we show that stimulation of agouti-related peptide-expressing (AgRP) neurons triggers a long-term depression (LTD) of spontaneous excitatory post-synaptic current (sEPSC) in adjacent pro-opiomelanocortin (POMC) neurons and in most of their distant synaptic targets, including neurons in the paraventricular nucleus of the thalamus (PVT). The AgRP-induced sEPCS LTD can be enhanced by fasting but blunted by satiety signals, e.g. leptin and insulin. Mice subjected to food-seeking tasks develop similar neural plasticity in AgRP-innervated PVT neurons. Further, ablation of the majority of AgRP neurons, or only a subset of AgRP neurons that project to the PVT, impairs animals' ability to associate spatial and contextual cues with food availability during food seeking. A similar impairment can be also induced by optogenetic inhibition of the AgRP→PVT projections. Together, these results indicate that the AgRP→PVT circuit is necessary for food seeking.