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ABI-H0731, a first-generation hepatitis B virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a phase 1b clinical trial and is currently being further evaluated in phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2-derived cell lines HepAD38 and HepG2-NTCP and primary human hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM)., ABI-H0731, a first-generation hepatitis B virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a phase 1b clinical trial and is currently being further evaluated in phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2-derived cell lines HepAD38 and HepG2-NTCP and primary human hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed covalently closed circular DNA (cccDNA) formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism-of-action studies indicated that ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogue (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing the premature release of relaxed circular DNA (rcDNA) before delivery to the nucleus, and thus prevents new cccDNA formation. ABI-H0731 exhibits pangenotypic activity and is additive to moderately synergistic when combined with an NrtI. In addition to its potency and novel mechanism of action, ABI-H0731 possesses drug-like properties and a preclinical pharmacokinetic profile supportive of once-daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV.