Sulfamethoxazole (SMX) is a sulfonamide antibiotic, widely used as curative and preventive drug for human, animal, and aquaculture bacterial infections. Its residues have been ubiquitously detected in the surface waters and sediments. In the present study, SMX dissipation and kinetics was studied in the natural water samples from Jiulong River under simulated complex natural conditions as well as conditions to mimic various biotic and abiotic environmental conditions in isolation. Structural equation modeling (SEM) by employing partial least square technique in path coefficient analysis was used to investigate the direct and indirect contributions of different environmental factors in the natural attenuation of SMX. The model explained 81% of the variability in natural attenuation as a dependent variable under the influence of sole effects of direct photo-degradation, indirect photo-degradation, hydrolysis, microbial degradation and bacterial degradation. The results of SEM suggested that the direct and indirect photo-degradation were the major pathways in the SMX natural attenuation. However, other biotic and abiotic factors also play a mediatory role during the natural attenuation and other processes. Furthermore, the potential transformation products of SMX were identified and their toxicity was evaluated.