Transactivation of Tropomyosin receptor kinase B (TrkB) by EGF leads to cell surface transport of TrkB, promoting its signaling responsiveness to brain-derived neurotrophic factor (BDNF), a critical process for proper cortical plate development. However, the mechanisms that regulate the transport of TrkB to the cell surface are not fully understood. Here, we identified Calnexin as a regulator for targeting TrkB either to the cell surface or toward autophagosomal processing. Calnexin-deficient mouse embryos show impaired cortical plate formation and elevated levels of transactivated TrkB. In Calnexin-depleted mouse neuronal precursor cells, we detected an impaired cell surface transport of TrkB in response to EGF and an impaired delivery to autophagosomes. Mechanistically, we show that Calnexin facilitates the interaction of TrkB with the ER-phagy receptor Fam134b, thereby targeting TrkB to ER-phagy. This mechanism appears as a critical process for fine-tuning the sensitivity of neurons to BDNF.