Cactus pear (Opuntia ficus-indica L.) is widely distributed in the arid and semi-arid regions throughout the world. In the last decades, the interest towards vegetative crop increased, and cladodes are exploited for nutraceutical and health-promoting properties. This study aimed at investigating the capacity of selected lactic acid bacteria to increase the antioxidant and anti-inflammatory properties of cactus cladodes pulp, with the perspective of producing a functional ingredient, dietary supplement or pharmaceutical preparation. Preliminarily, the antioxidant activity was determined through in vitro assays. Further, it was confirmed through ex vivo analysis on intestinal Caco-2/TC7 cells, and the profile of flavonoids was characterized. Cactus cladode pulp was fermented with lactic acid bacteria, which were previously selected from plant materials. Chemically acidified suspension, without bacterial inoculum and incubated under the same conditions, was used as the control. Lactobacillus plantarum CIL6, POM1 and 1MR20, Lactobacillus brevis POM2 and POM4, Lactobacillus rossiae 2LC8 and Pediococcus pentosaceus CILSWE5 were the best growing strains. Fermentation of cladode pulp with L. brevis POM2 and POM4 allowed the highest concentration of γ-amino butyric acid. Lactic acid fermentation had preservative effects (P<0.05) on the levels of vitamin C and carotenoids. Two flavonoid derivatives (kaemferol and isorhamnetin) were identified in the ethyl acetate extracts, which were considered to be the major compounds responsible for the increased radical scavenging activity. After inducing oxidative stress by IL-1β, the increased antioxidant activity (P<0.05) of fermented cladode pulp was confirmed using Caco-2/TC7 cells. Fermented cladode pulp had also immune-modulatory effects towards Caco-2 cells. Compared to the control, fermented cladode pulp exhibited a significantly (P<0.05) higher inhibition of IL-8, TNFα and prostaglandins PGE2 synthesis. The highest functional effect was found using ethyl acetate extracts. In conclusion, fermentation, especially with L. plantarum strains and L. brevis POM4, enhanced the antioxidant and immune-modulation features of cladode pulp.