Natural Deep Eutectic Solvent-Based Dispersive Liquid–Liquid Microextraction Coupled with UHPLC–MS/MS for the Determination of Antibiotic Residues in Food Products

Background/Objectives: The application of green analytical chemistry (GAC) principles is increasingly important in developing sustainable analytical practices for food safety monitoring. Natural deep eutectic solvents (NADESs) have emerged as green alternatives to conventional organic solvents. This study aimed to develop a sustainable analytical method for determining antibiotic residues in processed meat and frozen poultry products. Methods: A dispersive liquid–liquid microextraction (DLLME) procedure based on a NADES composed of anisaldehyde and decanoic acid (3:1, molar ratio) was coupled with UHPLC–MS/MS for the simultaneous determination of macrolides (clarithromycin, erythromycin), sulfonamides (sulfamethoxazole, sulfadimethoxine), and a fluoroquinolone (enrofloxacin) in food samples. Key extraction parameters, including NADES volume, vortex time, centrifugation time, sample amount, and pH, were optimized. The method was validated for linearity, accuracy, precision, and recovery and applied to real samples from the Saudi market. Results: The method showed excellent analytical performance, with good linearity (R2 ≥ 0.9982), recoveries of 84.1–99.4%, and RSDs ≤ 5.75%. The target antibiotics were successfully quantified in processed meat and frozen poultry samples, confirming applicability. In addition, a comprehensive evaluation using eight assessment tools confirmed the method’s environmental sustainability, practicality and innovation. Conclusions: The proposed NADES-based DLLME–UHPLC–MS/MS method is a rapid, sensitive, and eco-friendly alternative to conventional techniques for monitoring antibiotic residues in processed meat and poultry, supporting both food safety and GAC principles.