Amyloid beta (A beta) is the main culprit of neurotoxicity in Alzheimer's disease (AD); it causes the activation of several biochemical pathogenic mediators such as oxidative stress, which activate the pathogenesis of AD. The health preserving role and the AD preventing roles of natural antioxidants have recently caused them to draw considerable scientific and public attention. Exopolysaccharides (EPSs) are a type of antioxidant considered to have a robust in vitro and in vivo antioxidant potential that could be used for the development of effective and nontoxic medicines. Thus, in this study, we scrutinized the antioxidative properties of EPSs for the prevention of A beta mediated neurotoxicity in human neuroblastoma SH-SY5Y cells. Moreover, we examined their action on cellular viability, total antioxidant-oxidant status, antioxidant enzyme activities, and reactive oxygen species (ROS). The transcriptomic and proteomic changes regulating oxidative stress and antioxidant defense systems were also investigated. EPSs exerted a protective action on SH-SY5Y cells preventing A beta mediated neurotoxicity by maintaining total antioxidant-oxidant status, as well as the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) enzymes, hence lowering oxidative stress. EPSs exert their antioxidative effects by upregulating ERK1 , ERK2 , JNK , JUN , NF-kappa B/p65 , and p38 , as well as by downregulating AKT/PKB. Our results indicate that EPSs may offer a decent antioxidant potential to prevent oxidative stress mediated AD.