Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic fluorinated compounds recognized for their exceptional thermal and chemical stability. Since the 1950s, PFAS have been used in a wide range of consumer and industrial products, including non-stick cookware, water-repellent textiles, food packaging, and firefighting foams. Their persistence in the environment has led to widespread contamination of air, water, and soil—resulting in potential human exposure through ingestion, inhalation, or dermal contact. Growing research suggests links between PFAS exposure and adverse health outcomes, such as elevated cholesterol, liver damage, hormone disruption, and potential associations with certain cancers. In response, regulatory agencies like the FDA have taken steps to reduce human exposure—for example, by phasing out PFAS-based grease-proofing agents in food packaging. Additionally, AOAC has established Standard Method Performance Requirements (SMPRs) to guide PFAS testing in laboratories. This method describes the validated use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for detecting PFAS in food and packaging materials. The procedure includes sample homogenization, fortification with isotopically labeled internal standards, and extraction using acidified acetonitrile, followed by clean-up steps such as QuEChERS and solid-phase extraction. Detection is performed using multiple reaction monitoring (MRM) and retention time confirmation. Quantification is based on calibration curve comparisons and adjusted for dilution factors and sample mass. This robust approach delivers accurate, reliable PFAS data—supporting regulatory compliance and protecting consumer health.