As a cost-effective and wide-spectrum antibiotic with potent antibacterial properties, CAP (chloramphenicol) has been widely used in aquaculture and human medicine in recent years and is difficult to degrade by traditional biological treatment methods. In this study, the kinetics and economy in the oxidization of CAP by the VUV/PMS (peroxymonosulfate) process were investigated. The degradation of CAP was exhibited remarkably by the VUV/PMS process, compared with the individual effects of VUV and PMS. The degradation reaction followed pseudo-zero-order kinetics, with R2 of 0.993, indicating a relatively constant rate of degradation under certain conditions. Quenching experiments revealed that hydroxyl radicals (•OH) played a predominant role in the reaction. The degradation process was simulated effectively by a quadratic polynomial model, with degradation efficiency as the response variable and dosages of PMS, UV power, and retention time as independent variables, utilizing response surface methodology (RSM). The lowest total operating cost for CAP degradation was determined to be 0.417 USD/m³/order.