A method using innovative sample preparation was developed for determination of cocaine on banknotes. Aqueous extraction of cocaine from banknotes was performed using a sonication-enhanced technique. Quantitation of cocaine was achieved using high performance liquid chromatography (HPLC) with UV detection at 230 nm, whereas identification was accomplished utilizing gas chromatography with mass spectrometry (GC-MS). Multiple calibration techniques, including the external calibration method (ECM), internal standard method (ISM), and standard addition method (SAM) were incorporated into the experimental design to simultaneously determine cocaine contents and assess matrix effects. Statistical paired t tests confirmed that matrix effects were not significant with the sample preparation employed. No damage to the features of the banknotes was observed from the extraction procedure.Extraction efficiency, spike recovery, and detection limit were also determined. The unique experimental design allowed for ECM, ISM, and SAM to concurrently determine the contents of cocaine on banknotes collected around Metro-Detroit. The concentration range of cocaine was from 1.58 to 14.7 μg per note, with an average of 6.96 μg per note. The method is simple and suitable for drug analysis and forensic science applications.