This review, within the One Health framework, compiles information on plant-derived bioactive compounds and emphasises their multifunctional role in improving environmental, animal, and human health. These compounds support sustainable health and ecological stability by influencing biological and environmental processes. Data from literature research are combined to explain the mechanisms and potential uses of different key bioactive compounds. Mechanistic insights focus on their capacity to regulate oxidative stress, inflammation, and microbial balance, linking these effects to therapeutic benefits in human health, enhanced animal productivity, and environmental sustainability. These compounds show antioxidant, anti-inflammatory, antimicrobial, and metabolic activities, helping prevent chronic diseases, strengthen immunity, and reduce reliance on antibiotics and pollution. Examples like quercetin, resveratrol, and curcumin demonstrate their roles in modulating inflammatory and metabolic pathways to foster sustainable health and ecological balance. Bioactive compounds are linked to the One Health strategy, providing benefits across biological systems. Nonetheless, challenges such as variability, bioavailability, and standardization remain. Future directions should aim to develop sustainable extraction and formulation methods, leverage omics technologies and artificial intelligence for discovery and characterization, and foster industry partnerships to validate these compounds and secure global regulatory approval.

Background/Objectives: Mushroom-derived phenolic compounds are gaining attention as bioactive molecules with potential roles in gut microbiota modulation, intestinal health, and metabolic regulation. Although mushroom polysaccharides are well established as fermentable substrates, the contribution of fungal phenolics to microbiota–host interactions remains less defined. This review aimed to critically analyse the evidence supporting mushroom-derived phenolic compounds as emerging prebiotic-like modulators of gut microbiota, intestinal function, and host metabolism. Methods: A narrative critical review was conducted using scientific literature retrieved from PubMed, Scopus, Web of Science, and Google Scholar. Studies addressing phenolic profiling in edible and medicinal mushrooms, gastrointestinal digestion, colonic fermentation, microbial biotransformation, gut microbiota modulation, intestinal barrier function, inflammation, and metabolic outcomes were considered. Particular attention was given to chromatographic and mass spectrometry-based studies, in vitro digestion/fermentation models, mechanistic studies, animal experiments, clinical trials, systematic reviews, and meta-analyses. Results: Current evidence shows that mushrooms contain diverse phenolic compounds, mainly phenolic acids such as gallic, protocatechuic, caffeic, p-coumaric, ferulic, vanillic, syringic, and cinnamic acids. Due to limited small intestine absorption, a substantial fraction of these compounds may reach the colon, where they undergo microbial biotransformation into smaller phenolic metabolites. These metabolites may influence microbial ecology, support beneficial taxa, modulate short-chain fatty acid production indirectly, attenuate oxidative stress and inflammatory signaling, and contribute to intestinal barrier integrity. However, most evidence derives from in vitro and preclinical studies, while human data remain limited and are mainly based on whole-mushroom interventions. Conclusions: Mushroom-derived phenolic compounds are promising prebiotic-like modulators within the microbiota–metabolite–host axis. Nevertheless, their specific contribution cannot yet be quantitatively distinguished from that of other mushroom constituents, particularly β-glucans, chitin, and other fungal polysaccharides, because most available evidence derives from whole-mushroom matrices, crude extracts, or polysaccharide-rich preparations rather than isolated phenolic fractions. Future studies should compare whole mushroom preparations, polysaccharide-rich fractions, and standardized phenolic-rich extracts, integrating metabolomics, microbiome profiling, and well-designed clinical trials to clarify the relative mechanistic and therapeutic relevance of mushroom phenolics. Future studies should use standardized phenolic-rich extracts, metabolomics, microbiome analysis, and well-designed clinical trials to clarify their mechanistic relevance, clinical significance, and translational potential.