Alzheimer’s disease (AD) is the most common form of dementia being characterized by the progressive increase of memory deficits. Multiple factors such as amyloid-β (Aβ), tau hyperphosphorylation, inflammation, oxidative stress and infection have been reported to be involved in the pathophysiology of AD. Artemisinin is a first-line anti-malaria drug that has been used in the clinic for the last decades. Being able to cross blood brain barrier (BBB) its neuroprotective action has been reported along with several other beneficial effects such as antioxidant and anti-inflammatory properties that suggest its potential use for AD therapy. However, the therapeutic effect of artemisinin on AD is still unclear. In this study, we found that artemisinin improved the cognitive deficit and other abnormal changes in aged AD animal model 3xTg-AD mice. Artemisinin concentration-dependently reduced cell injury, improved neuronal cell function while decreased amyloid-beta deposition and hyperphosphorylation of tau protein in aged 3xTg-AD mice brains. Artemisinin also inhibited glial cells activation, inflammation and nec-apoptosis. Western blot assays showed that artemisinin stimulated the activation of ERK pathway. Consistent with this, artemisinin promoted the survival of SH-SY5Y cells incubated with Aβ1-42 in a concentration-dependent manner by preventing the accumulation of intracellular ROS, caspase 3 activation, LDH release and apoptosis. Artemisinin also stimulated the phosphorylation of ERK pathway in SH-SY5Y cells in a time and concentration-dependent manner and the inhibition of this pathway attenuated the protective effect of artemisinin. These data suggest that artemisinin neuroprotection against Aβ1-42 -induced damage and in 3xTg-AD mice may occur, at least in part, via the activation of the ERK pathway. Our findings strongly support the potential of artemisinin as a new multi-target drug that can be used in the prevention and treatment of AD.