A method to assay cocaine (COC), its metabolites benzoylecgonine (BZE), ecgonine (ECG), ecgonine methyl esther (EME), and benzoylnorecgonine (BNE), pyrolytic products anhydroecgonine (AEC) and anhydroecgonine methyl ester (AEME) and adulterant levamisole (LEV) was developed and validated by liquid chromatography-mass spectrometry (LC-MS) using a chemometric approach including a two-level factorial design in the screening step and face-centered central composite design (FCCCD) to achieve the optimization. The method was carried out on positive electrospray ionization (ESI⁺) with a flow of 1 mL min⁻¹ in isocratic mode consisting of 53% methanol and 47% ammonium acetate 10 mmol L⁻¹ pH 6.3. The chromatographic separation was obtained with a Phenomenex Luna C18(2) column (250 mm × 4.6 mm, particle size 5 μm), with the temperature set at 31 °C. Validation parameters such as specificity, linearity, precision and accuracy were evaluated. The method was linear over the concentration range of 1–100 ng mL⁻¹ for COC, AEME, EME, LEV, BZE and ECG and 5–100 ng mL⁻¹ for AEC and BNE. The method was successfully applied to identify and quantify the analytes.