The large-scale use of sulfonamide antimicrobials in human and veterinary medicine has seriously endangered the ecological environment and human health. The objective of this study was to develop and validate a simple and robust method for the simultaneous determination of seventeen sulfonamides in water using ultra-high performance liquid chromatography–tandem mass spectrometry coupled with fully automated solid-phase extraction. Seventeen isotope-labeled internal standards for sulfonamides were used to correct matrix effects. Several parameters affecting extraction efficiency were systematically optimized, and the enrichment factors were up to 982−1033 and only requiring about 60 min per six samples. Under the optimized conditions, this method manifested good linearity (0.05–100 μg/L), high sensitivity (detection limits: 0.01–0.05 ng/L), and satisfactory recoveries (79–118%) with acceptable relative standard deviations (0.3–14.5%,n= 5). The developed method can be successfully utilized for the determination of 17 sulfonamides in pure water, tap water, river water, and seawater. In total, six and seven sulfonamides were detected in river water and seawater, respectively, with a total concentration of 8.157–29.676 ng/L and 1.683–36.955 ng/L, respectively, and sulfamethoxazole was the predominant congener.