Natural chemicals have been considered as promising molecules in cancer treatment because of their broad spectrum of activities. Flavonoids show high affinity against key molecular targets associated with developing cancer, and tumor cells exhibit an inability to resist flavonoid treatment. Flavonoids are natural molecules synthesized during secondary plant metabolism that has protective activities against biotic and abiotic factors (animals, bacteria, and fungi) and are resistant to ultraviolet light, temperature, and solid minerals and contaminants. They have been purified from plants and synthetic molecules and have an antioxidant, antitumor, and cardioprotective activities in humans. The large flavonoid family includes polymethoxyflavones, which are extracted from the peels of citrus fruits such as Citrus nobilis, from which nobiletin (NOB) is obtained. The compounds derived from this promising anticancer chemical include 5-demethylnobiletin (5-DMN). These compounds inhibit a large number of targets that regulate the hallmarks of cancer by inducing apoptosis, cell cycle arrest, inhibition of proliferation, epithelial–mesenchymal transition, limiting migration, and angiogenesis. 5-DMN has exhibited potency in the regulation of anticancer activities. This review was conducted to summarize and compare the effects of NOB and 5-DMN on different types of cancer.