Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. β-Amyloid (Aβ) is widely accepted as the main neurotoxin that triggers mitochondrial-associated oxidative stress, leading to neuronal death in AD. Following our preliminary research on the neuroprotective effects of the brown alga Sargassum serratifolium, its major compounds, including sargaquinoic acid, sargahydroquinoic acid (SHQA), and sargachromenol, were investigated to elucidate the antioxidant and anti-apoptotic properties of Aβ_25–35-stimulated PC12 cells. SHQA exhibited the most potent effect on Aβ-induced mitochondrial-associated oxidative stress and apoptosis. In addition, the compound enhanced the expression and translocation of nuclear factor-E2-related factor 2 (Nrf2), while reducing the expression of cytoplasmic Kelch-like ECH-associated protein 1 (Keap1). Furthermore, the compound upregulated the expression of Nrf2-regulated antioxidant enzymes, including HO-1, NQO1, GCLc, GCLm, and TrxR1. Co-treatment with SHQA and LY294002, a specific PI3K inhibitor, inhibited nuclear Nrf2 expression and Akt phosphorylation, demonstrating that SHQA-mediated Nrf2 activation was directly associated with the PI3K/Akt signaling pathway. Mechanistic studies indicate that activation of the PI3K/Akt/Nrf2 pathway is the molecular basis for the neuroprotective effects of SHQA. In silico docking simulation revealed that SHQA established specific interactions with the key amino acid residues of PI3K, Akt, and Nrf2-Keap1 via hydrogen bonding and van der Waals interactions, which may affect the biological capacities of target markers. Overall, this is the first report of this novel mechanism of SHQA as a Nrf2 activator against Aβ-mediated oxidative damage, suggesting that the compound might be a potential agent for the prevention of AD.