<p>Neurodegenerative diseases (NDs) are conditions characterized by the progressive degeneration of neurons in the brain, leading to dysfunction in various aspects such as cognition, motor function, and overall quality of life. Leading causes of these disorders are various genetic factors, environmental influences, and aging. The exact pathophysiology is unclear. However, various biomarkers have been identified in NDs, including oxidative stress, neuroinflammation, neurofibrillary tangles, excitotoxicity, mitochondrial dysfunction, impaired protein homeostasis, α-synuclein, and tau hyperphosphorylation. Among them, Piezo1 is an ion channel that responds to mechanical stimuli, and it’s gaining attention for its involvement in the physiology of aging and various NDs. Additionally, it has been demonstrated to play a crucial role in modulating neurogenesis, synaptic remodeling, and cerebral blood flow. Piezo1 can also trigger neuroinflammation, oxidative stress, and neuronal damage through aberrant calcium influx and subsequent activation of pathways including MAPK, NF-κB, and YAP/ TAZ. In the present study, we have discussed molecular mechanisms and highlighted the cross-talk between oxidative stress and inflammation, focusing on Piezo1. Promising and evolving pharmacological strategies will be presented in detail with a critical consideration of current shortcomings and potential applications. Drug design and structural biology may have the potential to create more selective, brain-permeable, and safer modulators of Piezo1. Overall, Piezo1 is one of the promising mechanobiological targets, which may further broaden the scope of precision neuromodulation in complex NDs.</p> Graphical Abstract <p></p>