Background <p>The endoplasmic reticulum (ER) is a dynamic and essential cell organelle involved in the synthesis and correct folding of secretory and membrane-bounded proteins, as well as in preserving intracellular Ca²⁺ equilibrium.</p> Main body <p>During cellular stress, the deposition of unfolded or misfolded proteins in the ER lumen aggravates the cascade of the unfolded protein response (UPR), thus predisposing to ER stress. The interplay between ER and mitochondria exerts a pivotal role in coordinating intracellular Ca²⁺ signaling, lipid transfer, mitochondrial dynamics, autophagy initiation, and apoptotic processes. Persistent or unresolved ER stress could predispose to cellular perturbations as well as numerous disease pathogeneses, such as neurodegenerative, renal, hepatic, reproductive, and neoplastic disorders. Increasing evidence suggests that natural compounds possess therapeutic potential by modulating ER stress pathways. For example, curcumin and resveratrol can alleviate ER stress by enhancing protein-folding capacity, reducing oxidative stress, and regulating UPR signaling. These bioactive molecules can either mitigate ER stress and restore proteostasis or, conversely, intensify ER stress and apoptosis.</p> Conclusion <p>This review explores the multifaceted effects of natural products on ER stress-related mechanisms and their implications for disease treatment and prevention.</p> Graphical abstract <p></p>