Abstract Embedding isomers into crystalline skeletons with well‐defined spatial structures represents a feasible way to improve the catalytic activity for the oxygen reduction reaction (ORR). However, most research has been focused on the design of symmetric molecules, while studying asymmetric effects based on isomeric systems remains a major challenge. In this study, we introduced isomeric thiophene to regulate the ORR of one‐dimensional covalent organic frameworks (COFs), and further adjusted the molecular geometry configuration through asymmetric design, obtaining isomeric COF‐α with 2‐substituents and COF‐β with 3‐substituents. The intermediate adsorption ability and electronic states are precisely adjusted through asymmetric isomers, resulting in controllable chemical activity and excellent catalytic performance. Notably, the introduction of asymmetric thiophene units with 2‐substituents into a pure carbon‐based model provides a more favorable pathway for the hydrogen peroxide production process, resulting in a remarkable productivity of 11.20 mol g cat −1 h −1 , with a Faradaic efficiency of 90.16%. Moreover, theoretical calculations and in situ ATR‐FTIR experiments show that asymmetric thiophene skeletons can induce the activation of adjacent phenyl units, and precisely identify the benzene ring carbon atom (site‐8) connected to the thiophene unit as a potential active site. This study offers an approach to designing efficient electrocatalysts by adjusting asymmetric geometric isomers.