The QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method is a widely used approach for the determination of pesticide residues in food matrices, particularly in fruits. Developed by Anastassiades and coworkers, this method has revolutionized sample preparation by simplifying extraction and cleanup steps while ensuring high analyte recovery and minimal matrix effects. It relies on liquid-liquid partitioning with acetonitrile, followed by dispersive solid-phase extraction (d-SPE) to remove impurities, making it an efficient and cost-effective alternative to traditional methods. This chapter provides a detailed description of the QuEChERS procedure, including key variations, optimization strategies, and analytical considerations for pesticide residue detection in fruit-based samples. It also discusses its advantages, such as reduced solvent consumption and adaptability to different analytical techniques, including gas and liquid chromatography coupled with mass spectrometry. The method’s role in ensuring food safety and compliance with regulatory limits is highlighted, along with recent advancements and future perspectives for its application in the agro-food industry.