Plant foods are rich in phenolic compounds (PCs) that display multifaceted bioactions in health promotion and disease prevention. To exert their bioactivity, they must be delivered to and absorbed in the gastrointestinal (GI) tract, transported in circulation, and reach the target tissues. During the journey from ingestion to target tissues and final excretion, PCs are subjected to modifications by many factors during their absorption, deposition, metabolism and excretion (ADME) and consequently their bioefficacy may be modified. Consistent with all nutrients in foods, PCs must first be released from the food matrix through mechanical, chemical, and enzymatic forces to facilitate absorption along the GI tract, particularly in the upper small intestine section. Further, glycosylation of PCs directs the route of their absorption with glycones being transported through active transportation and aglycones through passive diffusion. After enteral absorption, the majority of PCs are extensively transformed by the detoxification system in enterocytes and liver for excretion in bile, feces, and urine. The journey of PCs from consumption to excretion appears to be comparable to many synthetic medications, but with some dissimilarities in their fate and bioactivity after phase I and II metabolism. The overall bioavailability of PCs is determined mainly by chemical characteristics, bioaccessibility, and ADME. In this review, factors accounting for variation in PCs bioavailability are discussed because this information is crucial for validation of the health benefits of PCs and their mechanism of action.