Atherosclerosis (AS), the formation of fibrofatty lesions in the vessel wall, is the primary cause of heart disease and stroke and is closely associated with aging. Disrupted metabolic homeostasis is a primary feature of AS and leads to endoplasmic reticulum (ER) stress, which is an abnormal accumulation of unfolded proteins. By orchestrating signaling cascades of the unfolded protein response (UPR), ER stress functions as a double-edged sword in AS, where adaptive UPR triggers synthetic metabolic processes to restore homeostasis, whereas the maladaptive response programs the cell to the apoptotic pathway. However, little is known regarding their precise coordination. Herein, an advanced understanding of the role of UPR in the pathological process of AS is reviewed. In particular, we focused on a critical mediator of the UPR, X-box binding protein 1 (XBP1), and its important role in balancing adaptive and maladaptive responses. The XBP1 mRNA is processed from the unspliced isoform (XBP1u) to the spliced isoform of XBP1 (XBP1s). Compared with XBP1u, XBP1s predominantly functions downstream of inositol-requiring enzyme-1?? (IRE1??) and transcript genes involved in protein quality control, inflammation, lipid metabolism, carbohydrate metabolism, and calcification, which are critical for the pathogenesis of AS. Thus, the IRE1??/XBP1 axis is a promising pharmaceutical candidate against AS.