Dioscoreophyllum cumminsii (Stapf) Diels leaves are widely used in the treatment of diabetes, obesity, and cardiovascular related complications in Nigeria. This study investigates the anti-inflammatory and antiobesity effect of aqueous extract of Dioscoreophyllum cumminsii leaves in high-fat diet- (HFD-) induced obese rats. HFD-fed rats were given 100, 200, and 400 mgkg−1 body weight of aqueous extract of Dioscoreophyllum cumminsii leaves for 4 weeks starting from 9th week of HFD treatment. D. cumminsii leaves aqueous extract reversed HFD-mediated decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose 6-phosphate dehydrogenase. Moreover, HFD-mediated elevation in the levels of conjugated dienes, lipid hydroperoxides, malondialdehyde, protein carbonyl, and DNA fragmentation in rats liver was lowered. HFD-mediated alterations in serum total cholesterol, triacylglycerol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were significantly reversed by the extract. The treatment of HFD-fed rats reduced the levels of insulin, leptin, protein carbonyl, fragmented DNA, and tumour necrosis factor-α and interleukin- (IL-) 6 and IL- 8 and increased the adiponectin level. This study showed that aqueous extract of Dioscoreophyllum cumminsii leaves has potential antiobesity and anti-inflammatory effects through modulation of obesity-induced inflammation, oxidative stress, and obesity-related disorder in HFD-induced obese rats.