Polyphenols are considered popular ingredients in the pharmaceutical and medical fields due to their preventive and therapeutic properties. However, the potential effects and mechanisms of action of individual polyphenols remain largely unknown. Herein, we analyzed recent data on the synthetic pathways, features, and similarity of the properties of quercetin, as the most famous flavonoid, and curcumin, a representative of curcuminoids that despite their anti-oxidant activity, also have a pro-oxidant effect, depending on the concentration and the cellular environment. This review focuses on an analysis of their anti-cancer efficacy against various cancer cell lines via cell cycle arrest (regulation of p53/p21 and CDK/cyclins) and by triggering the mitochondrial intrinsic (Bcl-2/Bax/caspase 9) apoptotic pathway, as well as through the modulation of the signaling pathways (PI3K/Akt, Wnt/β-catenin, JAK/STAT, MAPK, p53, and NF-ĸB) and their influence on the non-coding RNAs involved in angiogenesis, invasion, migration, and metastasis. The therapeutic potential of quercetin and curcumin is discussed not only on the basis of their anti-cancer effects, but also with regard to their anti-diabetic, anti-obesity, anti-inflammatory, and anti-bacterial actions.