This study explored the effect of fermentation on the antioxidant and anti-inflammatory activities of polysaccharides from seed coat of fermented and unfermented Annona squamosa seed. Fresh and ripe sugar apple fruits were collected from a tree in Ota-Efun, Osogbo, Nigeria (07o 32’ 30.2496” N, 04o 31’ 41.7036” E) and their identities were verified at IFE Herbarium, Department of Botany, Obafemi Awolowo, University, Ile-Ife, Nigeria. The seeds were collected and divided into two portions: fermented and unfermented. The coats of both the fermented and unfermented seeds were defatted with n-hexane separately. Polysaccharides were extracted from the defatted samples using cold and hot water procedure according to standard methods to give fermented seed coat polysaccharides and unfermented seed coat polysaccharides. Antioxidant and anti-inflammatory activities of the polysaccharides were investigated using standard methods. The reducing power, metal chelating, DPPH radical scavenging, inhibition of albumin denaturation, membrane stability potentials of the polysaccharides revealed the efficacy of the polysaccharides to take care of free radicals and maintain the integrity of the cell membrane and the fermented seed coat polysaccharide was the best. This study concluded that the polysaccharides from A. squamosa seed coat have great potential as antioxidant and anti-inflammatory agents to combat diseases related to oxidative stress, and fermentation enhanced the bioactivity of the polysaccharides.