Polymethoxyflavones (PMFs) are naturally found in citrus peels and other plants, with significant biological activities including anticancer, anti-inflammatory, and neuroprotective effects. This review updates the current understanding of PMFs, focusing on their metabolism, bioavailability, and health benefits. PMFs are primarily found in citrus peels, with nobiletin and tangeretin being the most abundant. They are metabolized in the gut by microbial enzymes, leading to demethylated derivatives with enhanced bioactivities. Despite their potential health benefits, there is limited data on PMF bioavailability and metabolism in humans. Clinical trials have shown some benefits of PMFs in improving cognitive function and reducing inflammation, but more research is needed to confirm their efficacy and safety. PMFs have shown promising effects in vitro and in animal studies, including anti-cancer, anti-inflammatory, and anti-atherosclerotic activities. However, their clinical application remains limited due to a lack of detailed pharmacokinetic data and human trials. Future research should focus on understanding PMF metabolism, bioavailability, and their potential therapeutic applications in humans.Polymethoxyflavones (PMFs) are naturally found in citrus peels and other plants, with significant biological activities including anticancer, anti-inflammatory, and neuroprotective effects. This review updates the current understanding of PMFs, focusing on their metabolism, bioavailability, and health benefits. PMFs are primarily found in citrus peels, with nobiletin and tangeretin being the most abundant. They are metabolized in the gut by microbial enzymes, leading to demethylated derivatives with enhanced bioactivities. Despite their potential health benefits, there is limited data on PMF bioavailability and metabolism in humans. Clinical trials have shown some benefits of PMFs in improving cognitive function and reducing inflammation, but more research is needed to confirm their efficacy and safety. PMFs have shown promising effects in vitro and in animal studies, including anti-cancer, anti-inflammatory, and anti-atherosclerotic activities. However, their clinical application remains limited due to a lack of detailed pharmacokinetic data and human trials. Future research should focus on understanding PMF metabolism, bioavailability, and their potential therapeutic applications in humans.