Alzheimer's disease (AD) is a severe neurodegenerative disease that includes cognitive and memory impairment. Multiple factors conduce to the progression of the AD, involving neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques. Inflammation, mitochondrial dysfunction and oxidative stress play a significant role in the progression of AD. It has been therefore suggested that the multifactorial nature of AD pathogenesis requires the design of antioxidant drugs with a broad spectrum of neuroprotective activities. For this reason, the use of natural products, characterized by multiple pharmacological properties is advantageous as AD-modifying drugs over the single-targeted chemicals. Artemether, a peroxide sesquiterpenoid lipid-soluble derivative of Artemisinin, has been used in the clinic as an anti-malarial drug for decade. Also, it exhibits potent anti-inflammatory and anti-oxidant activities. Here, we report the neuroprotective effects of Artemether towards Aβ-induced neurotoxicity in neuronal cultures. Artemether treatment attenuated the oxidative stress and conferred neuroprotection by inhibiting apo-necrosis of the cells. A temporal correlation was found between Artemether neuroprotection towards Aβ-induced neurotoxicity and AMPK/GSK3β phosphorylation activity and increased expression of activated Nrf2 signaling pathway. Artemether attenuated learning and memory deficits, inhibited cortical neuronal apoptosis and glial activation, inhibited oxidative stress through decreasing the lipid peroxidation and increasing the expression of superoxide dismutase enzymes, and reduced Aβ deposition and tau protein phosphorylation in the 3xTg AD mice. Moreover, Artemether induced phosphorylation of AMPK/GSK3β pathway which activated Nrf2 related signaling pathway, increasing the level of anti-oxidant protein heme oxygenase-1 (HO-1) in 3xTg AD mice. These activities most probably produced the anti-oxidant and anti-inflammatory and effects responsible for the neuroprotective effects of Artemether in 3xTg AD mice model. These findings make known that Artemether could represent a new drug for the treatment of AD disease.