Mitophagy, a process that removes damaged mitochondria, plays a key role in healthy cellular homeostasis. Decreased mitophagy contributes to the aging process and induction of mitophagy has been identified as a novel anti-aging mechanism for a few polyphenols. Cranberries have numerous health benefits which have been ascribed to their rich polyphenol content. Cranberries and cranberry polyphenols may also have the ability to induce mitophagy. To evaluate this hypothesis, the mitophagy inducing abilities of cranberry extracts and a few abundant cranberry polyphenols were examined in normal human fibroblasts, monitoring via confocal microscopy and Western blots. A cranberry extract (polyphenol content 120-125 mg/g) induced mitophagy with a maximum effective concentration of similar to 4 mu g/mL. Cranberry polyphenol subfractions, flavonols (0.4 mu g/mL) and anthocyanins (5 mu g/mL), induced mitophagy at low concentrations, while proanthocyanidins required a significantly higher concentration (50 mu g/mL) to achieve efficacy. When tested separately, the most abundant cranberry flavonols, quercetin, myricetin and kaempferol each induced mitophagy in a dose-dependent manner but were less efficient than the flavonol subfraction. A mixture of quercetin, myricetin and kaempferol at their most effective concentrations induced mitophagy comparable to the flavonol subfraction. These results suggest cranberry polyphenols induce mitophagy with flavonols requiring the lowest concentration to effectively induce mitophagy due to complementary or synergistic effects, shedding new light on the bioactivity of cranberries.