Zika virus (ZIKV) is a kind of mosquito-borne pathogen. Its infection can cause Zika virus disease. There is currently no specific treatment. Autophagy is a process in which cells maintain their own homeostasis and promote the reuse of intracellular substances and energy, but it is often hijacked by some viruses to promote their own replication. In this study, human hepatoma cell line (Huh7) was used as the target cell, and the mTagRFP-mWasabi-LC3 dual fluorescent reporter system was used to detect the formation of autophagosomes. Western blotting was used to detect the expression of autophagy markers LC3 and P62 proteins after ZIKV infection at different time points. Cells were pretreated with autophagy inhibitors (wortmannin and chloroquine), Beclin-1 specific short hairpin RNA (shRNA) and autophagy inducer rapamycin. Then their effects on viral protein expression and extracellular progeny virus titer were detected by Western blotting and virus plaque assay. The signaling pathways involved in the regulation of autophagy in ZIKV infection were detected by Western blotting. The results showed that the number of LC3-positive autophagosomes increased significantly in Huh7 cells after infection by ZIKV. The expression of LC3-II increased significantly from 12 h post infection, and P62 protein was significantly down-regulated at 48 h post infection. Both autophagy inhibitor treatments and interference of Beclin-1 expression could effectively inhibited ZIKV infection and the production of progeny viruses. Rapamycin treatment increased the content of extracellular progeny viruses (P<0.05). ZIKV infection enhanced the phosphorylation of adenosine 5’-monophosphate-activated protein kinase (AMPK) and TSC2, and reduced the phosphorylation of mammalian target of rapamycin (mTOR). The results demonstrate that ZIKV infection induces autophagy by activating the AMPK/TSC2/mTOR signaling pathway in Huh7 cells, and utilizes autophagy to promote virus replication and progeny virus production. It provides theoretical and experimental basis for the development of anti-ZIKV drugs based on autophagy-related molecules.