Deep eutectic solvents (DES), particularly natural DES (NADES), are emerging as transformative tools in natural product-based drug development by addressing persistent challenges related to solubility, stability, and sustainable extraction processes. This review systematically outlines recent advances, including the adoption of in silico methodologies utilizing sophisticated computational models, the development of novel extraction techniques, the strategic integration of multi-step purification approaches for compound isolation from DES matrices, and the application of specific formulations such as choline and geranic acid (CAGE) as functional components in drug delivery systems. Computational platforms like the conductor-like screening model for real solvents (COSMO-RS) and innovative extraction methods, such as ultrasound- and microwave-assisted techniques, have significantly improved the efficiency and predictability of DES applications, minimizing reliance on traditional trial-and-error methods. Among NADES, CAGE has demonstrated notable versatility, enhancing drug solubility, permeability, and stability, while also exhibiting intrinsic antimicrobial properties—qualities that render it particularly promising for transdermal and oral drug delivery. Nevertheless, critical challenges remain, including high viscosity, issues with large-scale production, and regulatory uncertainties. Future research directions emphasize the refinement of DES formulations for targeted therapeutic delivery, the integration of advanced technologies such as artificial intelligence (AI) and nanotechnology, and the establishment of standardized protocols to facilitate industrial and clinical adoption. Strong collaboration between academia and industry will be pivotal in overcoming these obstacles. Ultimately, by bridging traditional natural product research with innovative solvent technologies, DES are poised to support the advancement of greener, more sustainable pharmaceutical development. © 2025 Elsevier B.V.