Nitrophenols are toxic substances that present humans and animals with the risk of deformities, mutations, or cancer when ingested or inhaled. Traditional water treatment technologies have high costs and low p-nitrophenol (PNP) removal efficiency. Therefore, an ultraviolet (UV)-activated granular activated carbon supported nano-zero-valent-iron-cobalt (Co-nZVI/GAC) activated persulfate (PS) system was constructed to efficiently degrade PNP with Co-nZVI/GAC dosage, PS concentration, UV power, and pH as dependent variables and PNP removal rate as response values. A mathematical model between the factors and response values was developed using a central composite design (CCD) model. The model-fitting results showed that the PNP degradation rate was 96.7%, close to the predicted value of 98.05 when validation tests were performed under Co-nZVI/GAC injection conditions of 0.827 g/L, PS concentration of 3.811 mmol/L, UV power of 39.496 W, and pH of 2.838. This study demonstrates the feasibility of the response surface methodology for optimizing the UV-activated Co-nZVI/GAC-activated PS degradation of PNP.