Current therapies for hepatitis B virus (HBV) can effectively suppress viral replication but rarely lead to a functional cure, which creates a need for the development of new antiviral drugs with different mechanisms. The HBV core protein plays an essential role in multiple steps of the viral life cycle and has been proposed as a potential therapeutic target. EDP-514 is a novel HBV core inhibitor with a favorable pharmacokinetic and safety profile. Here, we describe the anti-HBV activities of EDP-514 in vitro and in a chimeric mouse model with humanized liver (PXB-mouse).