The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the "His-Phe switch" to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound <b>16g</b>, which is a potent TRβ agonist (EC<sub>50</sub>: 21.0 nM, 85.0% of the maximum efficacy of <b>1</b>) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβ<sup>H435R</sup> mutant. Then, we developed a highly efficient synthetic method for <b>16g</b>. Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. <b>16g</b> also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, <b>16g</b> is a well-characterized selective and mutation-sensitive TRβ agonist for further investigating its function in treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH).