Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by airway smooth muscle (ASM), enhances inflammation effects on airway contractility, supporting the idea that locally produced growth factors influence airway diseases such as asthma. We endeavored to dissect intrinsic mechanisms regulating endogenous as well as inflammation (TNFα)-induced BDNF secretion in ASM of non-asthmatic vs. asthmatic () humans. We focused on specific Ca²⁺ regulation- and inflammation-related signaling cascades, and quantified BDNF secretion. We find that TNFα enhances BDNF release by ASM cells, via several mechanisms relevant to asthma, including transient receptor potential channels TRPC3 and TRPC6 (but not TRPC1), ERK 1/2, PI3K, PLC and PKC cascades, rho kinase (ROCK), and transcription factors cAMP response element binding protein (CREB) and nuclear factor of activated T cells (NFAT). Basal BDNF expression and secretion are elevated in asthmatic ASM, and increase further with TNFα exposure, involving many of these regulatory mechanisms. We conclude that airway BDNF secretion is regulated at multiple levels, providing a basis for autocrine effects of BDNF under conditions of inflammation and disease, with potential downstream influences on contractility and remodeling.