Hepatitis B virus (HBV) infection causes serious liver diseases, and the development of effective drugs for chronic hepatitis B treatment remains an important step towards the eradication of HBV worldwide. Recently, our group designed paeonol-phenylsulfonyl derivatives and found that the compound 2-acetyl-5-methoxyphenyl 4-methoxybenzenesulfonate (6f) had the most potent antiviral effect against HBV, with an IC₅₀ value of 0.36 μM and a high selectivity index (SI; TC₅₀/IC₅₀) of 47.75. In this research, we modified compound 6f with a 2-aminothiazole scaffold and generated 13 novel paeonol derivatives by utilizing various benzoyl and acyl chlorides. Among this new generation, compound 2-(2-benzamidothiazol-4-yl)-5-methoxyphenyl 4-methoxybenzenesulfonate (8a) showed the highest SI value of 59.14 which exceeds those of compound 6f and lamivudine (3TC), a commercially available antiviral drug. Hence, we believe that our studies may offer some useful information for the development of antiviral medicines.