Sulfamethoxazole (SMX) is a veterinary drugs and feed additives, which has been frequently detected in surface waters in recent years. This paper investigated the kinetics, evolution of toxicity and antibiotic resistance genes (ARGs) of SMX in reactions with free chlorine (FC) to evaluate the fate of SMX in batch reactors and water distribution systems (WDS). In the range of investigated pH (6.3 – 9.0), the SMX degradation had the fastest rate at close to neutral pH. The chlorination of SMX could be described by the first-order kinetics, with specific second-order rate constants in batch reactors of (2.23 ± 0.07) × 102 M− s and (5.04 ± 0.30) × 101 M− s− for HClO and ClO−, respectively. And in WDS of (1.76 ± 0.07) × 102 M− s− and (4.06 ± 0.62) × 101 M− s−, respectively. The SMX degradation rate was also affected by pipe material, and the rate followed the order: stainless-steel pipe (SS) > ductile iron pipe (DI) > polyethylene pipe (PE). The flow rate from 0.7 to 1.5 m/s led to an increase of SMX degradation rate in DI, but the increase was limited. In addition, SMX could increase the toxicity of water initially, yet the toxicity reduced to the level of tap water after 2 hours chlorination. The relative abundance of ARGs (sul1 and sul2) of tap water samples was significantly increased under different conditions including only use SMX, chlorination products of SMX, or pretreatment with SMX followed by chlorination.