Hematite (α-FeO) has been commonly used as an eco-friendly catalyst for peroxymonosulfate (PMS) to generate free radicals (SO and/or •OH). However, the activation efficiency of PMS relies heavily on the conversion of Fe(III) to Fe(II) that is slow and rate-limiting. In this study, oxygen vacancies enriched α-FeO was prepared from thermally treated goethite (α-FeOOH) and employed as a PMS activator. Systematic characterization demonstrated that α-FeO with most abundant oxygen vacancies could be obtained by heating α-FeOOH at 300 °C. The as-prepared α-FeO exhibited excellent catalytic activity in activation of PMS for oxidation of sulfamethoxazole (SMX, k = 0.04 min). The SMX degradation rate was found to be positively correlated with the concentration of oxygen vacancies. Quenching experiments, EPR, LC/MS and XPS analysis revealed that singlet oxygen (O) was the predominant reactive oxygen species. The effects of pH, PMS dosage, catalyst loading, temperature, and anions on SMX degradation were comprehensively investigated. Moreover, the plausible degradation pathways of SMX in the α-FeO/PMS system were proposed. This work not only provides a valuable insight into the mechanism of PMS activation by α-FeO but also establishes a new strategy for the design of more efficient and practical iron-based catalyst for PMS activation.