Alzheimer’s disease (AD) is characterized by neurofibrillary tangles (NFTs), formed as a consequence of hyperphosphorylation of tau. The extent of phosphorylation of tau is regulated by protein phosphatases (PPs) like PP1, PP2A/Bα, PP2B and PP5. Interestingly, PP2A/Bα, is a major brain tau phosphatase which account for 70% of the dephosphorylation events in brain and, its activity is known to decrease by half under AD conditions. The down regulation of PP2A leads to hyperphosphorylation of Tau in the brains of AD patients. Hence, the process of reversal of tau phosphorylation needs to be achieved by the activation of PP2A, through specific molecules, as this could pave way towards development of novel therapeutics for AD. The key objective of the current study was thus to understand the affinities of various small molecules that could function as potential activators of PP2A. Molecules like Xylulose-5-Phosphate, Dihydroxy Phenylethanol, EGCG, Memantine, Sodium Selenate, Tetralone and Quinolone exhibit strong interactions across identified binding pockets of PP2A. The investigation not only confers that there could be more than one activation site in PP2A, but also offers clues as to how these molecules facilitate restoration of the phosphatases activity, thus proposing newer avenues for the treatment of AD.