Natural Deep Eutectic Solvents (NaDES) have been proposed as designer solvents for the green extraction of bioactive products from plants. Myrothamnus flabellifolia is a desiccation-tolerant medicinal shrub that has been widely studied for its phenolic properties; however, a NaDES-based approach for the extraction of phenolics has not been tested in this species. Our aim was thus to evaluate the extraction of phenolics from M. flabellifolia using four different NaDES with differing acidities using a non-targeted liquid chromatography-quantitative time-of-flight-tandem mass spectrometry (LC-QTOF-MS/MS) metabolomics approach. Anthocyanin pigments were quantified using targeted high-performance LC. Leaf material from M. flabellifolia was extracted in four different NaDES solutions (sucrose-fructose-glucose; proline-malic acid; sucrose-citric acid; and glucose-choline chloride), and the results were subjected to multivariate statistical analysis to evaluate the phenolic profiles of the different NaDES extracts. The NaDES were effective at extracting phenolic compounds from M. flabellifolia and also exhibited specificity in the suites of phenolics that they extracted, as indicated by principal component analysis. Using partial least squares-discriminant analysis, we were able to identify the phenolics that were most differentially abundant between the extracts, and a heatmap provided an indication of the types of phenolics that were extracted by the different NaDES. Furthermore, the NaDES also extracted several compounds not previously detected in M. flabellifolia using conventional organic solvents, demonstrating their use in compound discovery. The NaDES also differentially targeted anthocyanins, with the more acidic NaDES extracting higher quantities of anthocyanins and polymeric pigments. A green chemistry-based extraction technique using NaDES can thus effectively target phenolics in M. flabellifolia and offers a promising solution for future phytochemical investigations in medicinal plants using a highly efficient non-toxic solvent system that can be tailored to target particular compounds.