Several recent literature reports indicate the strong neuroprotective potential of synthetic heterosteroids, still search for potent, safer and effective neuroprotective steroidal molecules continues. In the current study, a new series of 17-oximino-16-substituted steroids (1-8) has been evaluated in MPTP-induced Parkinson's disease in mice and amyloid-β induced Alzheimer's disease in rats with an intention to discover an effective and efficient neuroprotective molecule. Behavioural studies followed by histopathological and estimation of the several neuroinflammatory biochemical parameters such as acetylcholinesterase, lipid peroxide, reactive oxygen, and nitric oxide species were carried out. A significant improvement in cognitive and locomotive dysfunctions was observed after treatment with these compounds. In silico molecular docking and simulation studies also correlated with the neuroprotective effects of the steroidal oximes 1-8 as strong binding affinities for TNF-α, IL-1β, AChE and β-secretase were seen. Among all the compounds, 4-pyridylidene (3) and 2-pyridylidene (1) substituted steroids displayed maximum neuroprotective efficacy in animal models of Parkinson's disease and Alzheimer's disease, respectively, and produced effects better than standard drugs. Hence, a new series of 16-arylideno-17-oximino steroids has been identified as potent neuroprotective agents which could be further explored structurally and clinically to discover and develop lead drug molecules useful for the treatment of Parkinson's and Alzheimer's disease.