Rational design of multifunctional catalysts to realize the synergistic combination of photocatalysis and peroxydisulfate (PDS) activation process is a promising approach for the effective removal of recalcitrant pollutants. Herein, metal-free covalent organic framework/g-C3N4 (COF/CN) van der Waals heterojunction was synthesized by the in-situ polymerization on g-C3N4. The van der Waals force and π-π conjugation effect contributes to promoting the interfacial migration and separation of photoinduced carries. The photocatalytic removal efficiency of sulfamethazine (SMT) by COF/CN was increased by 4.9 and 6.6-folds compared to those of COF and g-C3N4, respectively. In the optimal COF/CN-3/PDS/Vis process, SO4•− and 1O2 were identified as the major contributors to SMT degradation. The relationship between the molecular reactivity of sulfonamides (SAs) and reaction kinetics was elucidated by density functional theory (DFT) calculations at the electron level. The degradation rates and pathways depend on the electronic distribution and reactive sites of SAs with five- or six-membered heterocyclic ring substituents. The nonradical attack on the aniline and the breakage of C-N bond were the common traits of SAs degradation, whereas a unique Smiles-type pathway occurred in SAs with six-membered heterocyclic substituents. This work expected to promote the insight for the interaction between molecular structures of pollutants and reactive species in wastewater purification.