Objective: This study aimed to investigate the effect of Antarctic krill oil on zebrafish model of depression. Methods: The zebrafish (Danio rerio) model of depression was induced by 40 mg/L reserpine, and five groups, i.e., blank control group, model group, fluoxetine group, low-dose krill oil group and high-dose krill oil group were investigated and compared, buy using new tank test (NTT) and light dark box test (LDB). The central nervous system serotonin (5-HT), dopamine (DA), monoamine oxidase A (MAO-A) Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and systemic cortisol (COR) levels of the five groups were analyzed. Results: Reserpine 40 mg/L caused depressive behavior in zebrafish, while the addition of prawn oil reduced the this behavior, by increasing the levels of monoamine neurotransmitters including 5-HT and DA in the brain and decreasing the levels of MAO-A, IL-6 and TNF-α proinflammatory factors and systemic COR levels. Conclusion: Antarctic krill oil can improve the depression of zebrafish by reducing neuroinflammation and regulating neuroendocrine.