Covalent organic frameworks (COFs) can be rationally designed with functional organic ligands to improve the electrochemical responsiveness of the electrode toward certain medicinal compounds. In this study, we synthesized a COF-Ni electrocatalyst material, which is formed by covalent coupling of electron-rich 2,3,6,7-tetrakis (4-formylphenyl) tetrakis (4-imidazolyl) (TTF-4CHO) and hole-rich 5,10,15,20-tetrakis (4-aminophenyl) porphyrin nickel(II) (TAPP-Ni). The reasonable electron transfer path design, the large specific surface area of the COF and the physical properties of ordered nanopores, as well as the Ni-N4 bond as a highly active catalytic center, allow the COF-Ni material modified electrode to exhibit excellent sensing performance for acetaminophen (ACOP). The detection limit for ACOP is as low as 47.6 nM, with a linear range of 1-1500 μM, which is better than for most of the reported sensors. With superior interference resistance and good stability performance, COF-Ni is a highly suited electrode modification material for real-world sample detection, which provided a new perspective for application of COF materials in drug analysis.