Cell wall polysaccharides (CPSs) and polyphenols are major constituents of the dietary fiber complex in plant-based foods. Their digestion (by gut microbiota) and bioefficacy depend not only on their structure and quantity, but also on their intermolecular interactions. The composition and structure of these compounds vary with their dietary source (i.e., fruit or vegetable of origin) and can be further modified by food processing. Various components and structures of CPSs and polyphenols have been observed to demonstrate common and characteristic behaviors during interactions. However, at a fundamental level, the mechanisms that ultimately drive these interactions are still not fully understood. This review summarizes the current state of knowledge on the internal factors that influence CPS–polyphenol interactions, describes the different ways in which these interactions can be mediated by molecular composition or structure, and introduces the main methods for the analysis of these interactions, as well as the mechanisms involved. Furthermore, a comprehensive overview is provided of recent key findings in the area of CPS–polyphenol interactions. It is becoming clear that these interactions are shaped by a multitude of factors, the most important of which are the physicochemical properties of the partners: theirmorphology (surface area and porosity/pore shape), chemical composition (sugar ratio, solubility, and non-sugar components), and molecular architecture (molecular weight, degree of esterification, functional groups, and conformation). An improved understanding of the molecular mechanisms that drive interactions between CPSs and polyphenolsmay allow us to better establish a bridge between food processing and the bioavailability of colonic fermentation products from CPSs and antioxidant polyphenols, which could ultimately lead to the development of new guidelines for the design of healthier and more nutritious foods.