A series of new <i>O</i>-(substituted benzyl) phosphoramidate prodrugs of tenofovir for the treatment of hepatitis B virus (HBV) infections have been designed and synthesized. An investigation of structure-activity relationships revealed that the compound bearing an <i>o</i>-methylbenzyl group (<b>1a</b>) has the most potent <i>in vitro</i> anti-HBV activity. This prodrug (<b>1a</b>) was well-tolerated in KM mice via intragastric administration at a dosage of up to 1.5 g/kg. In DHBV-infected ducks, prodrug <b>1a</b> displayed a good inhibitory effect on the viral DNA replication in both the serum and the liver in a time- and dose-dependent manner and did not cause any necrosis, hemorrhage, or inflammatory response in the animal livers. Further investigation demonstrated that prodrug <b>1a</b> achieved a higher exposure of the bioactive metabolite (tenofovir diphosphate, TFV-DP) in the liver, the target organ for the treatment of HBV infection, than tenofovir alafenamide fumarate (TAF) did at an equimolar dose.