The present study, for the first time, reported more profound anti-inflammatory effects of EPA than DHA on microglia M1-induced neuroinflammation, such as EPA decreasing IL-1β, IL-6, TNF-α, but DHA only reducing IL-1β levels in the hippocampus of depression model, which should be taken into account for a better clinical outcome. Here, IL6 is linked to major depressive disorder.