This study aimed to develop multi-residue methods for the extraction of organic pollutants in mussels (Mytilus galloprovincialis), including 11 pharmaceuticals, 5 pesticides, 5 perfluoroalkyl substances (PFASs) and 2 illicit drugs. The combination of 4 different QuEChERS methods and 12 clean-ups (a total of 44 combinations) were tested. QuEChERS included acidified (AQ), non-acidified (SQ) and their miniaturized versions. The clean-ups included 6 different conventional dispersive solid phase extraction (dSPE) plus 2 enhanced matrix removal (EMR-Lipid) and 4 SPE procedures (including sorbents focused on phospholipid removal and polymer-based). After sample analysis via HPLC-MS/MS, the three methods that provided the best results were validated in terms of linearity, accuracy, precision, sensitivity and matrix effect. The methods selected were the combination of (i) SQ and EMR-Lipid, (ii) AQ and Z-sep+ bulk based dSPE and (iii) AQ and graphitized carbon black (GCB) based dSPE. Recoveries at two concentration levels (50 and 500 ng/g) ranged 53.9-124.0%, 58.5-124.0% and 60.3-127.0%, respectively and limits of detection (LODs) were <10 ng/g for most analytes using any of the methods. The three methods were tested in non-spiked mussel samples purchased in local markets, but organic pollutants were not detected in any sample.However, the methods probed to successfully extract a wide range of organic pollutants in mussel samples from the market and from bioaccumulation trials.