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• Axl-deficient (Axl−/−) mice exhibited increased susceptibility and decreased survival rate compared with WT mice under JEV infection. • JEV replication in Axl−/− primary neurons is significantly enhanced and the up-regulation of antiviral ISGs in Axl−/− neurons was significantly lower than that in WT neurons. • Axl might play a positive antiviral role in neurons through upregulating ISGs to inhibit JEV replication. Japanese encephalitis virus (JEV) causes the most commonly diagnosed viral encephalitis in Asia. JEV is a highly neurotropic flavivirus that can replicate efficiently in the brain. Axl belongs to the TAM (Tyro3, Axl, Mer) family, a group of tyrosine kinase receptors involved in the viral entry, micked as apoptotic bodies and regulation of innate immunity. However, the underlying mechanisms on its regulation in the neurons for JEV are unclear. Here, we found that Axl was upregulated in neurons after JEV infection. Unexpectedly, Axl deficient (Axl−/−) mice were more susceptible to JEV infection with increased viral loads in neurons. The RNA-sequencing analysis between the wild type neurons and Axl−/− neurons infected with JEV showed that many interferon-stimulated genes were downregulated in the Axl−/− neurons which innate immunity was attenuated largely. The rescue experiment in Axl−/− neurons indicated that Axl may be positively involved in the regulation of antiviral immunity. Taken together, our data demonstrated that Axl may play an antiviral role in JEV replication within neurons by modulating neuronal innate immunity. [ABSTRACT FROM AUTHOR]