Phycocyanin is a pigment-binding protein extracted from different algae for its great antioxidant and protecting properties. Uranium is a naturally radioactive metal showing many hazards effects on living organisms when exposed to it. The present study aims to show the effect of phycocyanin to decrease the ability of uranium to cross, accumulate, and distribute in six brain areas (cortex, cerebellum, hippocampus, striatum, midbrain, and hypothalamus) and demonstrated the expected neuroprotective role of phycocyanin against uranium intoxication in adult male albino rats. One hundred twelve rats are grouped as control, phycocyanin (PC), uranium (U), and PC+U group. Results showed that the daily administration of phycocyanin could decrease the uranium accumulation in the different brain areas. The daily intraperitoneal injection with uranium caused a significant decrease in norepinephrine (NE), dopamine (DA), serotonin (5-HT), and adenosine triphosphate (ATP), and reduced glutathione (GSH) accompanied by a significant increase in disulfide glutathione (GSSH), gamma aminobutyric acid (GABA), and glucose level. On the other hand, phycocyanin administration showed a significant change in malondialdehyde (MDA) and GSH level. The coadministration of phycocyanin in parallel with uranium injection showed that phycocyanin has a neuro-mitigation effect on uranium's adverse effect in all the tested parameters. The ameliorative effect of phycocyanin may be regarded as its high activity of scavenging the free radicals and its highly antioxidant effect.