Tumors occurring along the hypothalamus-pituitary axis receive axonal projection from neuroendocrine neurons, but it remains unclear whether neuroendocrine neuronal activity drives tumor expansion. Craniopharyngioma is a common suprasellar tumor with a propensity for invading the hypothalamus, leading to devastating endocrine and metabolic disorders. Here, we developed two autochthonous animal models that faithfully recapitulate the molecular pathology, clinical manifestations and transcriptomic profiles of papillary craniopharyngioma. Using high-throughput drug screening, we identified 74 compounds with potent anti-tumor efficacy. The administration of (S)-amlodipine besylate achieved tumor regression in vivo, potentially by abrogating calcium transients and neuron-to-tumor chemical transmission. Chemogenetic manipulation of neuroendocrine neuronal activity bidirectionally regulated tumor cell growth in our mouse model, suggesting that craniopharyngioma hijacks hypothalamic neurons to promote tumor progression. These findings deepen our understanding of suprasellar tumor biology and offer promising avenues for clinical exploration of effective chemotherapies.