A polyphenol antioxidant is a hypothesized type of antioxidant studied in vitro. Numbering over 4,000 distinct chemical structures mostly from plants, such polyphenols have not been demonstrated to be antioxidants in vivo.

In vitro at high experimental doses, polyphenols may affect cell-to-cell signaling, receptor sensitivity, inflammatory enzyme activity or gene regulation. None of these hypothetical effects has been confirmed in humans by high-quality clinical research, as of 2020^[update].

The main source of polyphenols is dietary, since they are found in a wide array of phytochemical-bearing foods. For example, honey; most legumes; fruits such as apples, blackberries, blueberries, cantaloupe, pomegranate, cherries, cranberries, grapes, pears, plums, raspberries, aronia berries, and strawberries (berries in general have high polyphenol content) and vegetables such as broccoli, cabbage, celery, onion and parsley are rich in polyphenols. Red wine, chocolate, black tea, white tea, green tea, olive oil and many grains are sources. Ingestion of polyphenols occurs by consuming a wide array of plant foods.

The regulation theory considers a polyphenolic ability to scavenge free radicals and up-regulate certain metal chelation reactions. Various reactive oxygen species, such as singlet oxygen, peroxynitrite and hydrogen peroxide, must be continually removed from cells to maintain healthy metabolic function. Diminishing the concentrations of reactive oxygen species can have several benefits possibly associated with ion transport systems and so may affect redox signaling. There is no substantial evidence, however, that dietary polyphenols have an antioxidant effect in vivo.

The “deactivation” of oxidant species by polyphenolic antioxidants (POH) is based, with regard to food systems that are deteriorated by peroxyl radicals (R•), on the donation of hydrogen, which interrupts chain reactions:

Phenoxyl radicals (PO•) generated according to this reaction may be stabilized through resonance and/or intramolecular hydrogen bonding, as proposed for quercetin, or combine to yield dimerisation products, thus terminating the chain reaction:

Consuming dietary polyphenols have been evaluated for biological activity in vitro, but there is no evidence from high-quality clinical research as of 2015^[update] that they have effects in vivo. Preliminary research has been conducted and regulatory status was reviewed in 2009 by the U.S. Food and Drug Administration (FDA), with no recommended intake values established, indicating absence of proof for nutritional value. Other possible effects may result from consumption of foods rich in polyphenols, but are not yet proved scientifically in humans; accordingly, health claims on food labels are not allowed by the FDA.

It is difficult to evaluate the physiological effects of specific polyphenols because a large number of individual phenolic compounds may occur in a single food and their fate in vivo cannot be measured.