Thiamethoxam is a second-generation neonicotinoid pesticide that is used worldwide. In this study, a three-dimensional electrode-enhanced ozone catalytic oxidation system (3DE-GAC-O3) was constructed to pretreat thiamethoxam wastewater, with granular active carbon as the particle electrode. The effects of catalytic oxidation time, current density, ozone concentration, initial thiamethoxam concentration, pH, and particle electrode dosage on thiamethoxam degradation were investigated. A response surface method based on the Box–Behnken design was employed to optimize the 3DE-GAC-O3 process. The results revealed that the 3DE-GAC-O3 system exhibited higher efficiency compared with the 3D electrode method, ozone catalytic oxidation, or 2DE-O3. The optimal operating conditions included a particle electrode dosage, ozone concentration, current density, solution pH, catalytic oxidation time, and initial thiamethoxam concentration of 18 g/dm3, 12 g/h, 25 A/m2, 7, 300 min, and 500 mg/dm3, respectively. The corresponding chemical oxygen demand removal rate reached 93.86 ± 0.95%. Thiamethoxam degradation followed a second-order reaction kinetics equation, and the rate constant decreased with increasing the initial thiamethoxam concentration. Free-radical quenching experiments indicated that both O2∙− and ∙OH were present within the 3DE-GAC-O3 system, with ∙OH being the predominant species. A GC-MS analysis revealed the formation of several intermediate products, which were characterized based on the mass fragmentation pattern. Additionally, a probable degradation pathway for thiamethoxam was proposed. Therefore, 3DE-GAC-O3 is an efficient method for the pretreatment of thiamethoxam wastewater.