Asiaticoside (AS), a triterpenoid saponin isolated from the Indian medicinal herb Centella asiatica is known to exert a neuroprotective effect by attenuating the neurobehavioral, neurochemical and pathological changes in animal models. However, its potential neuroprotection in rotenone-induced hemiparkinsonism which implicates phospholipid-mediated neurotransmission remains unclear. Therefore, we have investigated the neuroprotective effects of AS in rat model of ROT-infused hemiparkinsonism with respect to phosphoinositides-assisted cytodynamics and synaptic function. Adult male Sprague-Dawley rats (250–300 g) were distributed randomly into 6 groups, with 6 rats in each group: Sham control, Vehicle control (DMSO-0.1%), ROT-infused group (6 μg/μl/kg), AS-treated group (50 mg/kg/day), Drug (AS) control and Levodopa (L-DOPA)-treated group (6 mg/kg/day). At the end of the experimental period, the rats were sacrificed after performing behavioral analyses and the striatum regions were dissected out. Phosphoinositides (PI) are involved in intrinsic membrane signals that regulate intracellular membrane trafficking vesicle and endocytosis. We have assessed mRNA and protein expressions of genes involved in PI-mediated signaling and also in synaptic function (PI3K, PDK 1, PEBP, Stx 1A and TH) in addition to the levels of neurotransmitters and the enzymatic antioxidant profile. AS caused an improved working memory and motor co-ordination in the ROT group. It alters the levels of neurotransmitters (p < 0.01), the expression of mRNA and protein assessed which were significantly affected (P < 0.001) by rotenone, thus exhibiting its intervention in the progression of neurodegeneration. We demonstrate that AS can mediate distinct function in PI-assisted vesicle endocytosis, cytoprotective signaling and in the synaptic function thereby mitigating the ROT-infused hemiparkinsonism, however, its specific regulatory role remains to be unraveled.