Coffee represents one of the most traditionally consumed beverages worldwide, containing a broad range of human health–related compounds. According to previous studies, regular coffee consumption may display protective effects against colorectal cancer and other chronic diseases. The main goal of this research was to evaluate the bioaccessibility of phenolic content and variation in antioxidant capacity of three different types of coffee brews after simulated gastrointestinal digestion. This would allow to elucidate how antioxidant compounds present in coffee may exert their effect on the human body, especially in the colonic stage. Moreover, the content of bioactive compounds namely chlorogenic acids (CGAs, n = 11) and caffeine was also assessed throughout ultra-high-performance liquid chromatography followed by high-resolution Orbitrap mass spectrometry (UHPLC-Q-Orbitrap HRMS). The three main isomers of caffeoylquinic acid constituted the highest fraction of CGAs present in the samples, accounting for 66.0% to 70.9% of total CGAs. The bioaccessibility of coffee polyphenols significantly increased in digested samples from 45.9% to 62.9% at the end of the colonic passage, compared to the non-digested samples. These results point to the colonic stage as the major biological site of action of the active antioxidant coffee compounds.