The development of nanozymes with excellent intrinsic oxidase-like activity and specificity has received increasing interest. Graphdiyne (GDY) could be a promising choice for designing nanozymes with enhanced OXD-like activity due to its unique structure and properties. Herein, Co-N-GDY with high oxidase (OXD) activity but no peroxidase (POD) activity was synthesized by codoping of cobalt (Co) and nitrogen (N) into GDY and compared with other GDY-based nanozymes (including GDY, Co-GDY, and N-GDY). Upon analyzing the doping effect of Co and N on the OXD-like and POD-like activities, we found that the combination of Co and N in GDY played a significant role in enhancing the OXD-like activity, even reversed the POD-like activity of N-GDY to OXD-like activity of Co-N-GDY. The electrochemical experiment and the theoretical calculations provided an explanation for the mechanism and showed that the activity was closely linked to the reduction ability of O₂ or H₂O₂ on the nanozyme substrates, which was determined by the rate-determining step of the catalytic reaction.