Chrysobalanus icaco L. is an underexplored plant found in tropical areas around the globe. Currently, there is no apparent information regarding the effects C. icaco fruits may exert in vivo or potential role in health promotion. This study aimed at providing evidence regarding the in vivo influence of this fruit on antigenotoxicity, antimutagenicity, and oxidative stress in rats. Male Wistar rats were treated with 100, 200, or 400 mg/kg body weight (bw)/d C. icaco fruit for 14 d. Doxorubicin (DXR, 15 mg/kg bw, ip) was used for DNA damaging and as an oxidant to generate reactive oxygen species (ROS). Genomic instability was assessed by the comet assay and micronucleus (MN) test, while antioxidant activity was determined by oxidative burst of neutrophils. Chrysobalanus icaco fruit polyphenols were quantified and characterized by high-performance liquid chromatography coupled to a diode array detector and tandem mass spectrometer (HPLC-DAD-MS/MS). The concentrations of 19 chemical elements were determined by inductively coupled plasma-mass spectroscopy (ICP-MS). Significant amounts of polyphenols, magnesium, and selenium were found in C. icaco fruit. This fruit displayed in vivo antioxidant activity against DXR-induced damage in rat peripheral blood neutrophils, antigenotoxicity in peripheral blood cells, and antimutagenicity in bone-marrow cells and peripheral blood cells. Correlation analyses between endpoints examined indicated that the mechanism underlying chemopreventive actions of C. icaco fruit was attributed to inhibition of NADPH oxidase complex manifested as low levels of DNA damage in animals exposed to DXR. Data indicate that phytochemicals and minerals in C. icaco fruit protect DNA against damage in vivo associated with their antioxidant properties.