The present study aimed at investigating the lactic fermentation of cactus pear (Opuntia ficus-indica) fruit juice with the autochthonous and potentially probiotic strain Lactobacillus plantarum S-811. L. plantarum S-811 was able to quickly acidify the juice with a decrease in the pH from 5.5 to 3.7 and a production of 5.06 g l-1 of lactic acid. Fermentation of cactus pear juice led to conservation of its health-promoting properties and it markedly promoted antioxidant mechanisms in yeast cells, showing in a Saccharomyces cerevisiae model a protective effect of up to 11 times against H2O2 (4 mM), compared to yeasts not supplemented with the fermented juice. Administration of fermented juice to obese mice caused a significant decrease in the body weight gain and ameliorated the insulin resistance, hyperglycemia, and hyperlipemia that characterize obesity. These results reveal the potential of the cactus pear juice fermented with L. plantarum S-811 as a functional beverage for the prevention of obesity and related pathologies.