Abstract: Cistanche deserticola is a valuable medicinal herb with dual food and medicinal properties. Its primary active components are phenylethanoid glycosides (PhGs), including echinacoside and acteoside. PhGs possess diverse pharmacological activities, including antioxidant, neuroprotective, anticancer, hepatoprotective, and cognitive-enhancing effects. However, their poor oral absorption and rapid metabolism result in low bioavailability, limiting their clinical application and therapeutic efficacy. Existing research indicates that the low bioavailability of PhGs primarily stems from their high polarity, low intestinal absorption rate, and rapid metabolic clearance. This paper synthesizes multiple studies to summarize the general patterns of PhGs metabolism in vivo. Their metabolism primarily involves esterase hydrolysis, gut microbiota conversion, and glucuronidation reactions, which collectively determine their in vivo stability and duration of therapeutic effect. Delivery technologies such as liposomes (Lip), solid lipid nanoparticles (SLN), and nanoparticles (NPs) can significantly enhance the stability and solubility of PhGs. Nano-carriers provide effective strategies for chemical structure protection and targeted controlled release, reducing hydrolysis rates, enhancing membrane permeability, and prolonging retention time in vivo. This synergistically increases absorption and efficacy. Achieving spatiotemporal control for localized release of active substances is crucial for enhancing the functional activity and application potential of phenethyl glycosides. This review systematically integrates chemical, biological, and pharmaceutical research findings on PhGs, identifying key mechanisms and optimization principles influencing their pharmacological effects. It provides clear theoretical foundations and technical directions for developing novel functional foods and clinical drugs based on PhGs. This research offers expanded options for clinical treatment and health management through the creation of new functional foods or pharmaceuticals derived from PhGs.