Dietary intake of omega-3 fatty acids found in fish has been reported to reduce the risk of Alzheimer’s Disease (AD). Stearidonic acid (SDA), a plant-based omega-3 fatty acid, has been targeted as a potential surrogate for fish-based fatty acids. However, its role in neuronal degeneration is unknown. This study was designed to evaluate effects of SDA on Amyloid-β(A-β)-induced neurotoxicity in rat hippocampal cells. Results showed that SDA effectively converted to eicosapentaenoic acid (EPA) in hippocampal cells. Aβ-induced apoptosis in H19-7 cells was protected by SDA pretreatment as evidenced by its regulation on the expression of relevant pro- and anti-apoptotic genes, as well as the inhibition on caspase activation. SDA also protected H19-7 cells from Aβ-induced oxidative stress by regulating the expression of relevant pro- and anti-oxidative genes, as well as the improvement in activity of catalase. As for Aβ/LPS-induced neuronal inflammation, SDA pretreatment reduced the release of IL-1β and TNFα. Further, we found that the anti-Aβ effect of SDA involves its inhibition on the expression of amyloid precursor protein and the regulation on MAPK signaling. These results demonstrated that SDAs have neuroprotective effect in Aβ-induced H19-7 hippocampal cells. This beneficial effect of SDA was attributed to its antiapoptotic, antioxidant, and anti-inflammatory properties.