Dysregulation of glucose and lipid metabolism is an important pathophysiological basis for the development of metabolic syndrome. Polyphenols derived from medicinal and edible plants have attracted considerable attention for their structural diversity, multiple molecular targets, and long history of dietary use. This review summarizes the structural characteristics and structure–activity relationships of major polyphenol classes, including flavonoids, phenolic acids, and polymeric polyphenols, and discusses how structural differences contribute to their distinct effects on digestive enzyme inhibition, antioxidant activity, and metabolic signaling. On this basis, the potential mechanisms by which polyphenol combinations regulate glucose and lipid metabolism are discussed, including the concurrent modulation of multiple targets such as α-amylase, α-glucosidase, and pancreatic lipase; structural complementarity among polyphenols with different structural characteristics and metabolic regulatory properties; coordinated regulation of AMPK-, PPAR-, and PI3K/Akt-related signaling pathways, with potential temporal complementarity between rapid metabolic responses and more sustained transcriptional regulation; and modulation of gut microbiota and absorption and metabolic processes that may influence the overall effects of polyphenol combinations. Quantitative approaches for evaluating synergistic effects, including the combination index (CI) and Bliss model, as well as evaluation strategies at the in vitro, cellular, animal, and human levels, are also reviewed. Particular attention is given to current limitations, including insufficient quantitative assessment of synergy, limited causal evidence for the proposed mechanisms, and a lack of human intervention studies. In contrast to reviews of plant polyphenols in general, this review focuses on polyphenols from medicinal and edible plants with a long history of dietary use, and examines their combined effects from the perspectives of structural complementarity, gut microbiota-mediated biotransformation, and pharmacokinetic interactions. The applicability and limitations of different methods for assessing synergistic effects are also compared, with the aim of providing a reference for future research on polyphenol combinations from medicinal and edible plants and for the development of related functional foods.