The combination of chemometric and green metric tools adds up to synergistic effects at method development, being highly compatible with green analytical chemistry (GAC). In the present study, both strategies were applied for the development of an ultrasound-assisted extraction mediated by Natural Deep Eutectic Solvent (UA-NADES). The Box–Behnken Design combined with multiple responses and desirability functions allowed the effective optimization of the proposed extractive methodology using an alternative green solvent. Considering the obtained results, a green UA-NADES extraction and chromatographic determination of phenolic compounds in Lactuca sativa samples were developed. Finally, the recent Analytical GREEnness metric approach was applied, and scores were compared with recent miniaturized approaches for the extraction/determination of phenolic compounds in lettuce. The results of the AGREE analysis highlight the greenness of the proposed methodology.