Mangiferin, the main active substance of the mango tree bark (Mangifera indica L.), is known for its use in natural medicine, not only as a health enhancing panacea or adjunct therapeutic, but also for brain functions improvement. In this context, we deemed it worthwhile to establish whether mangiferin could traverse into the brain after systemic administration; an essential piece of information for the rational use of a compound as a neurotherapeutic, remaining so far inconclusive regarding mangiferin. We addressed this issue by studying recoverability of mangiferin in membrane and cytosolic fractions of rat brain homogenates after its intraperitoneal administration in a dose of 300 mg/kg. We used three preparations of mangiferin of decreasing purity to find out whether its penetration to the brain could have to do with the possible presence of contaminants. The qualitative methods of thin-layered-chromatography and UV/VIS spectrophotometry were employed in this study. The results were clearly negative, as we failed to trace mangiferin in the brain fractions with either method, which makes it unlikely that the compound traverse the blood-brain barrier after being systemically administered. We conclude that it is improbable that mangiferin could act via direct interaction with central neural components, but rather has peripheral, target specific functions which could be secondarily reflected in brain metabolism.