The kidneys and brain share similarities in anatomy and vaso-regulation and exhibit clinical interactions in various diseases. To investigate the probable mechanism of kidney to brain crosstalk, we developed an in vivo model of renal injury in mice through intoxication with the oxidative stress inducer, tBHP. Proteinuria, abnormalities in the renal tubules and KIM1 activation were found in tBHP intoxicated animals. Due to this renal pathophysiology, various pro-inflammatory molecules (TNF-α, IL-1β, IL-6, ICAM-1, VCAM-1) especially TNF-α, entered into the brain from kidneys, triggering cerebral inflammatory cascades leading to behavioral anomalies in association with membrane lipid peroxidation, BBB disruption and brain morphological alterations. Moreover, increased levels of reactive oxygen species, decreased antioxidant enzyme activity and an altered GSH/GSSG ratio were found in both these organs. Here, we introduced mangiferin as a protective molecule because of its anti-inflammatory and antioxidant properties. Mangiferin via inhibition of apoptosis and activation of the PI3K/Akt pathway protected the kidneys. It restored the deleterious phenomena in the damaged brain by downregulating the JNK and p38MAPK mediated pro-apoptotic cascade and activating the intracellular antioxidant thioredoxin, thereby protecting against tBHP induced nephropathy mediated neuropathophysiology.