Flavonoids are classified into subclasses of polyphenols, a multipurpose category of natural compounds which comprises secondary metabolites extracted from vascular plants and are plentiful in the human diet. Although the details of flavonoid mechanisms are still not realized correctly, they are generally regarded as antimicrobial, anti-fungal, anti-inflammatory, anti-oxidative; anti-mutagenic; anti-neoplastic; anti-aging; anti-diabetic, cardio-protective, etc. The anti-cancer properties of flavonoids are evident in functions such as prevention of proliferation, metastasis, invasion, inflammation and activation of cell death. Tumors growth and enlargement expose cells to acidosis, hypoxia, and lack of nutrients which result in endoplasmic reticulum (ER) stress; it triggers the unfolded protein response (UPR), which reclaims homeostasis or activates autophagy. Steady stimulation of ER stress can switch autophagy to apoptosis. The connection between ER stress and cancer, in association with UPR, has been explained. The signals provided by UPR can activate or inhibit anti-apoptotic or apoptotic pathways depending on the period and grade of ER stress. In this review, we will peruse the link between flavonoids and their impact on the endoplasmic reticulum in association with cancer therapy.