The endoplasmic reticulum (ER) is a specialized organelle crucial for protein folding and trafficking, highly sensitive to changes in intracellular homeostasis and extracellular stimuli. Misfolded proteins in the ER trigger the unfolded protein response (UPR), a set of adaptive signaling pathways to restore protein-folding homeostasis. Recent studies have linked reactive oxygen species (ROS) production to ER stress and UPR, highlighting the critical role of redox balance in cellular processes. ER stress and oxidative stress coexist in various pathologies, but their interplay remains poorly understood. This review discusses the generation of ER stress and oxidative stress, their signaling pathways, and their cross-talk in cellular homeostasis and apoptosis. It also explores how these stresses contribute to human diseases, including metabolic disorders, inflammatory conditions, and neoplasms. Understanding the mechanisms underlying the interaction between ER stress and oxidative stress provides insights for developing novel therapeutic strategies.The endoplasmic reticulum (ER) is a specialized organelle crucial for protein folding and trafficking, highly sensitive to changes in intracellular homeostasis and extracellular stimuli. Misfolded proteins in the ER trigger the unfolded protein response (UPR), a set of adaptive signaling pathways to restore protein-folding homeostasis. Recent studies have linked reactive oxygen species (ROS) production to ER stress and UPR, highlighting the critical role of redox balance in cellular processes. ER stress and oxidative stress coexist in various pathologies, but their interplay remains poorly understood. This review discusses the generation of ER stress and oxidative stress, their signaling pathways, and their cross-talk in cellular homeostasis and apoptosis. It also explores how these stresses contribute to human diseases, including metabolic disorders, inflammatory conditions, and neoplasms. Understanding the mechanisms underlying the interaction between ER stress and oxidative stress provides insights for developing novel therapeutic strategies.