Neuroendocrine prostate cancer (NEPC), a lethal subset of the disease, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that neuropilin 2 (NRP2) is upregulated in both de novo and therapy-induced NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology and NEPC cell aggressive behaviors. NRP2 silencing reduced or even eliminated NEPC tumor xenograft growth. Mechanistically, NRP2 engages in reciprocal crosstalk with AR, where NRP2 is a direct transcriptional target inhibited by AR, and in turn, suppresses AR signaling by downregulating the AR transcriptional program and confers resistance to enzalutamide. Moreover, NRP2 physically interacts with VEGFR2 through the intracellular SEA domain to activate STAT3 phosphorylation and subsequently SOX2, thus driving NEPC differentiation and growth. Together these results characterize NRP2 as a driver of NEPC and suggest NRP2 as a potential therapeutic target in NEPC.