<p>A key pathophysiological feature of cancer and many chronic diseases is low-grade persistent inflammation. Given the importance of this condition, there is growing interest in natural products with both antiproliferative and anti-inflammatory properties, such as polyphenols. The antiproliferative and immunomodulatory activities of free and encapsulated polyphenol extracts from six Mexican <i>Opuntia</i> (<i>Cactaceae</i>) species have been determined. Extracts from six <i>Opuntia</i> peel varieties were assessed for antiproliferative activity using Caco2 and THP1 cells, as well as for anti-inflammatory potential through nitric oxide scavenging using RAW 264.7 cells. Both the free and encapsulated polyphenol extracts exhibited antiproliferative and nitric oxide-scavenging activities, although encapsulation greatly enhanced these activities. Results show that the peel from <i>Opuntia</i> fruits, a waste byproduct of little value so far, is a source of bioactive compounds with health-promoting properties. This may represent a revalorization of <i>Opuntia</i> crops and wild species that grow in arid and semiarid regions.</p>