MOF anodes were especially prepared with dual-ligand and S/N crosslinking atoms for tetracycline hydrochloride (TCH) electrocatalytic degradation. Results showed S(HTTP)-Ni-N(HAB) and N(HITP)-Ni-S(BHT) exhibited high electrocatalytic performance with 100% TCH degradation in 10 min, which were superior to that of S(HTTP)-Ni-S(BHT) and N(HITP)-Ni-N(HAB). The experimental and DFT calculation results jointly unraveled that the electron delocalization created by adjacent S/N crosslinking atoms facilitated the electron conduction and produced positive-charged Ni sites for the improved generation of ·O2− and ·OH radicals. The positive contributions of ·O2− and ·OH radicals then proved the degradation pathways of TCH. In addition, extended experiments on various conditions and pollutions highlighted the application potential of S/N hybrid MOF anodes. The final results provided new insight into MOF anode design and preparation via large cardinal ligand and crosslinking atom adjustment for environmental application.