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To investigate the role and underlying mechanism of miR-185-5p in hepatitis B virus (HBV) expression and replication.The relative levels of hepatitis B surface antigen and hepatitis B e antigen were detected by enzyme-linked immunosorbent assay (ELISA). The HBV DNA copies in the cultures medium were measured by RT-qPCR. The HBV large surface antigen promoter (S1p) activity was analyzed by luciferase reporter assay. The target relationship between miR-185-5p and ELK1 was identified by bioinformatics analysis and EGFP fluorescent reporter assay. The ELK1 expression was determined by RT-qPCR and Western blot.miR-185-5p significantly decreased HBV large surface antigen promoter activity and subsequently the production of HBV proteins and HBV DNA copies in vitro. Further, we identified the ETS transcription factor ELK1 is a target of miR-185-5p. Overexpression and knockdown experiments showed overexpression of ELK1 stimulated HBV large surface antigen promoter activity and promoted the production of HBV proteins and HBV DNA copies, whereas knockdown of ELK1 has the opposite effects. Moreover, the rescue of ELK1 expression reversed the suppression of miR-185-5p on HBV replication and gene expression. Further mechanistic study showed that the ETS binding sites within the HBV large surface antigen promoter are required for the repression effect of miR-185-5p on HBV.There are few reports about the interaction between miRNAs and the transcription from HBV S1p, we found that miR-185-5p decreases HBV S1p activity by targeting ELK1, which may provide a promising therapeutic strategy for HBV infection.