A rapid and sensitive hydrophilic interaction liquid chromatography (HILIC)-tandem mass spectrometry method was developed and fully validated for the simultaneous determination of the antidiabetic drug metformin and six further pharmaceuticals (atenolol, gabapentin, levofloxacin, ciprofloxacin, propranolol and trimethoprim) in influent and effluent wastewater. Five deuterated related compounds were used as internal standards in order to control the extraction, injection and ionization variability. Two solid phase extraction methods and Oasis HLB 1cc cartridge, using only 1 mL sample with acid or basic pH-value were optimized and compared in order to match the specificity of both influent and effluent wastewater matrixes. The most important challenge was to efficiently extract the polar compound metformin from the aqueous matrix. This was possible by adjusting the sample pH to 10. On the other hand, the adjustment to acid pH prevents metformin binding on the SPE cartridges. Metformin was so directly recovered after passing through the cartridge and injected in the HPLC–MS/MS system without any other preparation. These two methods present advantages and drawbacks, but are both applicable to wastewater samples. The method with extraction at pH 3 was applied to influent wastewater samples and metformin concentrations higher than 625 ng/L. On the other hand, the extraction method at pH 10 with a lower limit of quantification for metformin of 156 ng/L was successfully applied to effluent water and to surface water samples. Both methods were fully validated. Limits of quantification were sufficiently low to provide good analytical performances for the determination of all drugs in both influent and effluent wastewater. Wastewater samples collected from six different wastewater treatment plants in Germany were analyzed. All analytes were present in influent samples at concentrations above the lower limit of quantification LLOQ, particularly metformin which presents concentrations up to 300 μg/L.