As an antibiotic drug, sulfamethoxazole (SMX) is a nitrogen- and sulfur-containing heterocyclic compound as well as an endocrine disruptor that is difficult to biodegrade. Not only can it exist stably in soil and water bodies for a long time, but it also can cause potential harm to the environment and human health. Therefore, it is of great practical significance to adopt effective treatment methods to alleviate the damage of sulfadiazine drugs on microorganisms and accelerate their degradation rate in water. Cobalt-mediated peroxymonosulfate (PMS) activation is considered an effective approach that can generate reactive species for the degradation of pollutants. Herein, a solvent-free intercalation method was developed to obtain ultra-thin hemi-crystalline Co₃O₄/SiO₂ nanosheets, in which crystallinity could be regularly controlled by the calcination atmosphere. Hemi-Co₃O₄/SiO₂ possessed enriched oxygen vacancies (O_V), precise peroxymonosulfate (PMS)-binding affinity and rapid Co²⁺/Co³⁺ conversion activity, which triggered both radical and nonradical reactions for efficient SMX oxidation. The SMX removal efficiency of hemi-Co₃O₄/SiO₂ (rate constant = 1.101 min⁻¹) was 4.95 times higher than that of the regular cobalt oxide. Radical (˙O₂⁻ and SO₄˙⁻) and non-radical (¹O₂) pathways were verified to be key mechanisms in the degradation. It was found beyond expectation that ˙O₂⁻ was produced only on amorphous and hemi-crystalline Co₃O₄, which was nearly absent on highly crystalline Co₃O₄. This work provides insights into the critical relationship between crystallinity regulation and the activity of advanced oxidation process (AOP) catalysts, clarifies the diverse pathways of the catalysts of different crystallinities, and provides guidance for rational catalyst design for sustainable water decontamination technologies.