Developing efficient and low-cost catalysts in peroxymonosulfate (PMS)-based advanced oxidation processes is vital but challenging. Here, a series of Co,Fe co-doped MoS2 with abundant S vacancies were prepared and utilized as PMS activators. The OTC removal efficiency (92.0%) in 1-Co,Fe-MoS2/PMS system was significantly higher than that (53.5%) in MoS2/PMS system. SO4•–/•OH, O2•−, and 1O2 played dominant roles, while high-valent metal and electron transfer mechanism played limited roles for OTC removal in both systems. The contributions of reactive species in 1-Co,Fe-MoS2/PMS system ranked as follows: 1O2 > SO4•–/•OH > O2•−, while that was O2•− > SO4•–/•OH >1O2 in MoS2/PMS system. Co and Fe doping promoted the generation of S vacancy in MoS2. Co(II)/Co(III), Fe(II)/Fe(III) and Mo(IV)/Mo(VI) all contributed to the activation of PMS, but Co and Fe sites were the major active sites of 1-Co,Fe-MoS2. Moreover, 1-Co,Fe-MoS2 was deposited on a polytetrafluoroethylene membrane, and exhibited excellent catalytic effect for OTC removal via a flow-through setup. Thus, this study provided a promising Co,Fe-MoS2/PMS process for organic pollutant removal.