This study reports the preparation of an affordable Ni-doped CoMoO4 catalyst (NiXCo1−XMoO4 (X = 0–1)) via a hydrothermal method by substituting Co with Ni and investigated the performance and mechanism of NiXCo1−XMoO4 catalyzing peroxymonosulfate (PMS) to degrade organic pollutants for the first time. Based on characterization, it can be observed that the synthesized Ni0.5Co0.5MoO4 catalyst exhibited excellent surface properties and structural stability. Under optimal conditions, Ni0.5Co0.5MoO4 and PMS synergistically achieved over 95% degradation of chloroquine phosphate (CQP) within 20 min, demonstrating superior performance. The degradation system maintained high efficiency under interference different interfering substances in aqueous media, exhibiting excellent tolerance and practicality. Elemental analysis and mechanistic studies of the catalyst showed that Ni doping promoted the reduction between Co2+/Co3+ and Mo4+/Mo6+, which is critical for catalyst durability and reusability. The quenching experiment and electron paramagnetic resonance (EPR) show that the 1O2 generated through non-free radical pathways represented the predominant reactive species. A total of 19 intermediates were detected by LC-MS during degradation and possible pathways for CQP degradation were proposed and toxicity evaluation. After 5 cycles, the catalyst still showed good stability. Ni0.5Co0.5MoO4 challenges including poor activation, metal ion leaching and low recovery of transition metal catalysts were addressed. This work offers new insights for the design of atom-doped spinel catalysts for catalytic oxidation and mechanism research. The Ni0.5Co0.5MoO4/PMS catalytic system can be extended to the treatment of other organic pollutants and even applied in the processing of high-concentration organic wastewater that requires rapid treatment, offering broader prospects for practical applications.