Nonalcoholic steatohepatitis (NASH) is a progressive stage of nonalcoholic fatty liver disease (NAFLD) and is characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. While there are currently no approved therapies for NASH, the thyroid hormone receptor β (THR-β), primarily expressed in the liver, is emerging as an effective molecular target for the treatment of NASH. However, the adverse cardiac and bone effects mediated by thyroid hormone receptor α (THR-α) need to be minimized. Herein, we reported the discovery of a series of novel THR-β agonists featuring pyrrolo[3,2-<i>b</i>]pyridin-5-one skeletons based on structure-based drug design. Further optimization led to compound <b>15</b>, which exhibited higher potency and selectivity for THR-β over THR-α compared to clinical drug <b>MGL-3196</b>. More significantly, an excellent liver-to-serum ratio of 93:1 was observed for compound <b>15</b>. We believe that the high hepatic concentration of compound <b>15</b> may result in no cardiotoxicity.