The objective of this study was to evaluate the effects of an ethanolic extract of the bark of bacupari (Garcinia brasiliensis - EEB) on the abundance of intestinal microbiota, concentration of short-chain fatty acids (SCFAs), oxidative stress, and inflammation in obese rats fed a high-fat diet (HFD). Male Wistar rats were divided into three groups: an HFD-fed obese control group, a group fed HFD plus EEB (BHFD) at a dose of 300 mg per animal per day (42 mg 7-epiclusianone and 10.76 mg morelloflavone), and a lean control group fed an AIN-93 M diet for 8 weeks. EEB decreased (p < 0.05) the abundance of organisms belonging to the phyla Firmicutes and Proteobacteria, and increased (p < 0.05) the concentration of propionic acid. Liver concentrations of malondialdehyde, nitric oxide, resistin, and p65 nuclear factor-kappa B p65(NF-κB) decreased (p < 0.05), while the expression of heat shock protein (HSP)72 and catalase increased (p < 0.05) with the consumption of EEB. Moreover, computational molecular modeling studies involving molecular docking between the main constituents of EEB, 7-epiclusianone and morelloflavone, and NF-κB suggested its inhibitory activity, thus corroborating the experimental results. The consumption of EEB may therefore be a promising strategy for the beneficial dietary modulation of the intestinal ecosystem, thereby countering oxidative stress and inflammation in obese rats. This activity is attributable to the presence of bioactive compounds that act individually or synergistically in the scavenging of free radicals or in the inflammatory process.