The aim of this study was to analyze the aqueous and ethanolic extracts of fruits (pomegranate, jambolan, jackfruit, physalis and bitter melon) residues regarding the assessment of α-amylase inhibition, cytotoxicity and bioaccessibility of phenolic compounds, flavonoids and antioxidants after the in vitro gastrointestinal digestion and fermentation with probiotics and phenolic compounds by UFLC-DAD. The extracts showed a high rate of α-amylase inhibition, presenting a possible antidiabetic potential. The cytotoxicity test showed good response at the tested concentrations (10, 50, 100 and 1000 μg/mL). The contents of phenolics total after digestion and the fermentation, ranged from 483 ± 4 to 9816 ± 80 mg GAE/100g. ORAC method showed a significant increase in the antioxidant activity with bioaccessibility index above 100% for most extracts, ranging from 221 ± 9 to 868 ± 34%. The bioaccessibility of the catechin, protocatechuic acid, gallic, vanillic, propyl gallate and pyrocatecol compounds has been reported firsthand for some residues. Thus, bioactive compounds present in the fruit residues can be released during gastrointestinal digestion, being good sources of natural antioxidants and with promising potential benefits for human health.