A reliable method was developed for the simultaneous extraction and determination of sixteen sulfonamides (SAs), nine quinolones (QLs), three macrolides (MLs), four tetracyclines (TCs), nine azoles, two neonicotinoids, and dimethoate in sediments using ultrasonic-assisted extraction (USE) followed by solid phase extraction (SPE) clean-up and high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The USE solvents (seven solvents or their combinations), SPE clean-up conditions (e.g. types of SPE cartridges, dilution volumes, and addition of Na₂EDTA), and LC-MS/MS parameters were optimized. Quantification was performed by an external standard method using matrix-matched calibration curves. Recoveries of the target compounds ranged from 40% to 127% (except enrofloxacin and marbofloxacin), with relative standard deviations <18.4% (n = 5). The method detection limits were 0.01 to 0.45 ng g⁻¹ dry weight for all the target analytes. The method was successfully applied to analyze the selected chemicals in surface sediments collected from the Jiulong River Estuary, Fujian, China. The concentrations of the target compounds in the sediments (dry weight) were relatively low, with 0.15–2.9 ng g⁻¹ of Σ₁₆SAs, 1.0–16.6 ng g⁻¹ of Σ₉QLs, 0–2.6 ng g⁻¹ of Σ₃MLs, 1.3–17.5 ng g⁻¹ of Σ₄TCs, and 0.77–6.8 ng g⁻¹ of Σ₁₂ pesticides.