The chapter thoroughly explores the comprehensive relationship between endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) in neurological diseases, alongside an investigation into the modulatory effects of natural compounds on ERS. ERS-induced UPR is pivotal in neurodegenerative diseases like Alzheimer’s and Parkinson’s, where aberrant protein accumulation challenges cellular homeostasis. Under pathological conditions, UPR is activated to restore endoplasmic reticulum (ER) function. However, sustained or dysregulated UPR exacerbates neuronal dysfunction, contributing to neurodegeneration. This intricate process involves chaperone activation and a reduction in protein synthesis to alleviate ERS. Natural compounds, such as phytochemicals and herbal extracts, have emerged as promising modulators of ERS. These compounds exhibit diverse mechanisms, including antioxidant properties and the induction of ER chaperones, to mitigate ERS and support cellular resilience. By attenuating neuroinflammation and promoting overall neuronal health, natural compounds present potential therapeutic avenues. The exploration of ERS-induced UPR and the influence of natural compounds represent a compelling area for innovative interventions targeting protein homeostasis in the ER, offering hope for neuroprotective strategies in the complex landscape of neurological disorders. This chapter serves as an essential resource for researchers, clinicians, and enthusiasts seeking a deeper understanding of the mechanistic intricacies underlying ERS in neurodegenerative disorders and the therapeutic potential of natural compounds in restoring neuronal health.