Bergenia ciliata (Haw) Sternb. possess immunomodulatory, anti-inflammatory, antioxidant, anti-urolithiatic, wound healing, anti-malarial, anti-diabetic and anti-cancer properties. Moreover, the methanolic extracts of the rhizomes of the plant were found to demonstrate beneficial neuroprotective effects in the intracerebroventricular streptozotocin-induced model in rats. Thus, the present study was undertaken to further explore the neuroprotective potential of the aqueous (BA) and methanolic extracts (BM) of B. ciliata through various in-vitro and in-vivo studies. Both the extracts at all tested concentrations i.e. 50–50,000 ng/mL did not cause any significant reduction of cell viability of SH-SY5Y cells when tested for 48 h when assessed through MTT and resazurin metabolism- based cell viability assays. The pre-treatment with the extracts could confer significant (p < 0.001) and dose-dependent protective effects against NMDA induced injury in SH-SY5Y cells. BM [IC₅₀: 5.7 and 5.19 μg/mL for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) respectively] led to more potent inhibition of both the enzymes as compared to BA (IC₅₀: 227.12 and 23.25 μg/mL for AChE and BuChE respectively). BM also proved to be a 1.85-fold better scavenger of the DPPH free radicals as compared to BA. Thus, BM was taken further for the evaluation of the beneficial effects of 14-day pre-treatment in rats in the scopolamine (2 mg/kg, i.p.) induced amnesia model at 125, 250 and 500 mg/kg, p.o. BM pre-treatment at 250 and 500 mg/kg could significantly ameliorate the cognitive impairment (p < 0.001), inhibit AChE (p < 0.001) and BuChE (p < 0.05) activity, restore GSH levels (p < 0.05) in serum and brain homogenates and recover the morphology of hippocampal neurons back to normal. Moreover, the BM administration at 500 mg/kg also showed beneficial effects through the significant (p < 0.05) reduction of Aβ_1-42, phosphorylated tau (p-tau) and GSK-3β immunoreactivity in the brain homogenates of the intracerebroventricularly streptozotocin (ICV STZ) injected rats as observed from the results of the ELISA assays. The outcomes of the study unveiled that BM exerts its beneficial effects through prevention of NMDA induced excitotoxic cell death, dual cholinesterase inhibition, antioxidant activity coupled with the reduction of the immunoreactivity for the Aβ_1–42, p-tau and GSK-3β indicating its potential to be screened further for various other models to determine the exact mechanism of action.