<p>Alternative matrices are increasingly used in postmortem toxicology when conventional specimens such as femoral blood are unavailable. However, quantitative multi-matrix methods covering a wide range of tissues remain limited. This study describes the development and fit-for-purpose validation of a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for quantification of 20 forensically relevant drugs in human and porcine postmortem matrices. Analytes and internal standards were extracted by methanol-based protein precipitation, followed by reversed-phase chromatography gradient separation and quantitation using a linear ion trap consisting of a quadrupole mass filter. A solvent calibration curve was used to analyze all matrices in a single analytical run. Validation was performed according to a modified fit-for-purpose approach focusing on accuracy, precision, selectivity, carry-over, matrix effect, dilution feasibility, and stability. Acceptance criteria were fulfilled for 89.3% of analyte–matrix combinations under standard criteria and 96.7% after predefined fit-for-purpose adjustments. Porcine matrices showed analytical performance comparable to human tissues, supporting their use as surrogate matrices for method development and validation. The developed LC–MS/MS method enables quantification of drugs across a broad range of alternative postmortem matrices using a single extraction and calibration approach. The method is intended for fast, reliable, and resource-efficient multi-matrix studies rather than absolute quantification in individual matrices and provides a practical tool for the investigation of postmortem redistribution processes.</p>