Centella asiatica (L.) Urban (Family: Apiaceae) is a perennial herb that has been used to elevate mood, improve memory, treat wounds and manage kidney-related ailments in African traditional medicine practice. This study evaluated the potential benefits of C. asiatica (CA) on diabetes-induced stress in kidney and brain of rats. Following the induction of diabetes mellitus (DM), rats were orally treated with vehicle, CA or Metformin daily for 14 days. After treatment, renal and brain levels of inflammatory cytokines, TNF-α, IFN-γ, IL-4, and IL-10 were assessed. Oxidant and antioxidant biomarkers were also evaluated. Phyto-compounds in the crude methanol extract of CA were analyzed by Gas Chromatography–Mass Spectroscopy. Diabetes increased malondialdehyde (MDA) concentration by 39%; elevated levels of TNF-α (44%) and IFN-γ (20%); and reduced the antioxidant status in the kidney in comparison to normal control rats. In the brain, diabetic control rats had significantly greater levels of MDA, TNF-α, and IFN-γ (182%, 40%, and 20%, respectively) in addition to the lowered antioxidant status when compared to normal control rats. However, treatment with CA significantly reduced the renal levels of MDA (33%), TNF-α (78%), and IFN-γ (42%) while that of IL-10 increased by 18% when compared to diabetic control rats. In the brain, CA treatment elicited significant reductions in MDA (37%), TNF-α (30%), and IFN-γ (37%) levels while those of IL-4 and IL-10 increased by 94% and 20% respectively. In addition, the renal and brain antioxidant status was significantly boosted by CA treatment. Several medicinal compounds including ascorbic acid, asiatic acid, oleanolic acid, stevioside, stigmasterol, and α-humulene were identified in the crude extract of CA. Findings from this study suggest CA may protect diabetic tissues from stress via antioxidant and anti-inflammatory mechanisms that can be useful in the management of diabetic complications.