The inflammation-induced the excessive proliferation and migration of airway smooth muscle (ASM) cells in the airway wall contribute to airway remodeling in asthma pathogenesis. SET domain-containing lysine methyltransferase 7 (SETD7) has emerged as one of the key regulators of inflammation. Yet, the function of SETD7 in regulating inflammation-induced ASM cell proliferation and invasion remains unclear. In the present study, we aimed to investigate the function of SETD7 in regulating ASM cell proliferation and invasion induced by tumor necrosis factor (TNF)-α in vitro. Our results showed that SETD7 expression was upregulated in ASM cells stimulated with TNF-α. Silencing SETD7 significantly decreased TNF-α-induced ASM cell proliferation and migration, while SETD7 overexpression exhibited the opposite effect. Notably, silencing SETD7 decreased the activation of nuclear factor (NF)-κB and reduced the expression of CD38 induced by TNF-α. Blocking NF-κB activation significantly abrogated the promotional effect of SETD7 overexpression on CD38 expression. Moreover, overexpression of CD38 partially reversed the inhibitory effect of SETD7 silencing on TNF-α-induced ASM cell proliferation and migration. Overall, these results demonstrate that SETD7 regulates TNF-α-induced ASM cell proliferation and migration through modulation of NF-κB/CD38 signaling, suggesting a potential role of SETD7 in asthma airway remodeling.