The presence of pharmaceutically active compounds (PhACs) in aquatic biota has been received much less attention than their presence in surface or waste water, and it was not until the mid-2000s, this gap started to be addressed. Here, we present SQUEEZe (Solid-liQuid Ultrasound Extraction with QuE Z-Sep/C18 as dispersive clean-up): a fast method for analysis of the trace 47 PhACs in fish muscle. Compared to our previously reported method [1], it offers alternatives with improvements in recoveries, number of analytes, sample volume and solvent used. The key aspects of this method are:•The ultrasound extraction was performed with acetonitrile/isopropanol 0.1% V/V formic acid. A clean-up step using QuE Z-Sep/C18 sorbents was employed to reduce lipid content of the extracts and further matrix effects in the detection of the analytes.•A HPLC separation with a Kinetex EVO C18 packed column in 11 min was optimized. MS and MS/MS data were collected using SWATH acquisition on the SCIEX X500R QTOF in (+)-ESI mode.•The method validated at 3 different concentrations levels: 5, 25 and 50 ng/g fish. It presented good intraday/interday reproducibility and absolute recoveries ≥ 60% for majority of analytes in composite homogenate muscle matrix of Squalius cephalus.•10 out 47 compounds were detected in fish samples.