Oxidative stress is an important contributor to the pathogenesis of Alzheimer's disease (AD). The overproduction of reactive oxygen species observed in AD patients results in the loss of mitochondrial function, altered metal ion homeostasis, lipopolysaccharide metabolism disorder, reduced anti-oxidant defense, increased release of inflammatory factors, and the aggravation and accumulation of amyloid-beta and tau hyper-phosphorylation, which directly cause synaptic and neuronal loss and lead to cognitive dysfunction. Thus, oxidative stress proves to be a fundamental part of AD development and progression, suggesting the potential benefits of anti-oxidant-based therapies for AD. In this study, we found that a water-soluble extract of Artemisia annua (WSEAA), a traditional Chinese herbal medicine, has a strong anti-oxidant function. We also found that WSEAA is able to improve the cognitive function of 3xTg AD mice. However, the mechanisms and molecular targets underlying WSEAA action are still not known. In order to uncover the potential molecular mechanisms involved, we used a combination of network pharmacology and different experimental approaches. Obtained results revealed key genes (such as AKT1, BCL2, IL-6, TNF-α and BAX) and signaling pathways (like PI3K-AKT and BCL2/BAX) are closely associated with the biological processes responding to oxidative stress. Further verification of the survival/anti-oxidant effects of WSEAA in vitro and in vivo showed that the extract has anti-oxidatant/neuronal survival action against H2O2-induced damage, and is thus able to prevent the cognitive decline and pathological changes of 3xTg transgenic (3xTg) mice via the regulation of key target-genes and pathways, such as PI3K-AKT and BCL2/BAX, related to survival/apoptosis. Our findings strongly indicate the potential of WSEAA for the prevention and treatment of AD.