Tau hyperphosphorylation at Ser396/404 and its adverse neurological effects have been evident in animal models of cerebral malaria (CM). As a counter measure, quest for novel pharmacological therapeutics to ameliorate tau hyperphosphorylation in neurodegeneration and restore behavioural and cognitive functions with high efficacy in CM has been at the forefront of neurobiological studies. In this study, using experimental model of cerebral malaria (ECM), we administered four different polycyclitol derivatives, SR4 (01-04) as an adjunctive to ARM therapy resulting in alleviation of cdk5/p25 based tau signaling cascade and restoration of long-term memory. Limitations of scyllo-inositol and rational to synthesize these polycyclitols efficiently has also been captured in the backdrop. Initially, we studied long-term, short term memory and novelty based learning by conducting Barnes maze, T-maze and novel object recognition task in treated animal groups. The cognitive outcomes of SR4-02 (15) and SR4-04 (18) treated groups exhibited better learning and memory compared to SR4-01 (16) and SR4-03 (17) groups. We further evaluated cdk5/p25 and tau phosphorylation protein expression using western blotting, immunohistochemistry and Golgi-cox staining to study neuronal arborization pattern. Immunohistochemical analysis of hippocampal and cortical tissue regions showed reduced phospho tau expression in SR4-03 (17) and SR4-04 (18) groups compared to CM group. Similarly, Golgi-cox images showed increased neuronal density in Cornus Ammonis (CA1) and CA3 regions of hippocampus and cortex of SR4-02 (15), SR4-03 (17) and SR4-04 (18) treated mice. Overall, based on our findings, polycyclitol derivatives have the potential to alleviate tau levels and restore cognition in ECM.