<p>Engineering active sites in a controllable manner plays a critical role in developing catalysts with desired catalytic performance. A reliable and tunable molecular engineering strategy is presented to boost the oxygen reduction reaction (ORR) performance of single-atom catalysts (SACs) by manipulating the steric hindrance effect of metalloporphyrins. The results demonstrate that the metalloporphyrin molecules with four tert-butylphenyl groups as steric hindrance moieties can be used to prepare various SACs with targeted active sites on conductive carbon black (CB). It is found that the single iron catalyst on CB prepared using tert-butylphenyl iron-porphyrins as a precursor (denoted as t-Fe-800/CB) exhibits significantly enhanced ORR performance compared with the Fe-800/CB catalyst prepared from unsubstituted iron-porphyrin. Moreover, the t-Fe-800/CB catalyst exhibits superior ORR performance relative to t-Mn-800/CB and t-Co-800/CB with different metal centers, indicating that the intrinsic ORR activity originates from single Fe sites. The remarkable ORR properties are mainly attributed to the enhanced intrinsic activity and density of Fe active sites, as well as improved conductivity and mass transfer induced by the steric hindrance effect. The optimized t-Fe-800/CB catalyst also delivers impressive performance in both flexible and aqueous Zn–air batteries. This study offers a new perspective for the development of advanced SAC electrocatalysts for energy conversion applications.</p>