In modern water industry, trace organic contaminants are usually subjected to multiple treatment barrier. Structural modification triggered by pretreatment (e.g., prechlorination) may influence the further transformation and fate of contaminants in downstream treatment unit processes. However, our knowledge on this aspect is still limited. In this contribution, we investigated the chlorination of chloroxylenol (PCMX), an antimicrobial agent extensively used during COVID-19 pandemic, and the photoreactivity of its halogenated derivatives. Our results indicated that chlorination of PCMX mainly occurred through electrophilic substitution to give chlorinated products, including Cl- and 2Cl-PCMX. Addition of bromide (Br−) shifted the halogenated derivatives to bromine-containing products such as Br- and 2Br-PCMX. Owing to the bathochromic and “heavy atom” effects of halogen substituents, these products have increased light absorption and photoreactivity. Toxicity evaluation suggested that these halo-derivatives also have much higher persistence, bioaccumulation, and toxicity (PBT) than the parent PCMX. Results of this contribution advance our understanding of the transformation of PCMX during chlorination and the photochemical activity of its halogenated derivatives in sequential UV disinfection process or sunlit surface waters.