In recent years, plant-origin bio-active compounds in foods (staple crops, fruit, vegetables, and others) have been gaining interest, and processes to consider them for public health recommendations are being presented and discussed in the literature. However, at times, it may be challenging to demonstrate causality, and there often is not a single compound–single effect relationship. Furthermore, it was suggested that health benefits may be due to metabolites produced by the host or gut microbiome rather than the food constituent per se. Over the years, compounds that were investigated were shown to increase gut microbial diversity, improve endothelial function, improve cognitive function, reduce bone loss, and many others. More recently, an additional and significant body of evidence further demonstrated the nutritional role and potential effects that plant-origin bio-active compounds might have on intestinal functionality (specifically the duodenal brush border membrane, morphology, and the abundance of health-promoting bacterial populations). Hence, the special issue “Dietary Plant-Origin Bio-Active Compounds, Intestinal Functionality, and Microbiome” comprises 11 peer-reviewed papers on the most recent evidence regarding the potential dietary intake and effects of plant-origin bio-active compounds on intestinal functionality, primarily in the context of brush border functional proteins (enzymes and transporters), mineral (and other nutrients) dietary bioavailability, and the intestinal microbiome. Original contributions and literature reviews further demonstrated the potential dietary relevance that plant bio-active compounds hold in human health and development. This editorial provides a brief and concise overview that addresses and summarizes the content of the Dietary Plant-Origin Bio-Active Compounds, Intestinal Functionality, and Microbiome special issue.