Objective To explore the therapeutic effects of docosahexaenoic acid(DHA) on depression, and its influence on the expression of caspase-3 in hippocampal neuron. Methods A total of 50 SD rats were randomly divided into 5 groups (control, model, fluoxetine, DHA, combination group), 10 rats in each group. SD rats were given different stimuli for 21 days to set up unforeseeable chronic stress depression model. After 21 days, the changes of behaviors in forced swimming test and morphology change in CA1, CA2 and CA3 in hippocampal neurons were observed. The change of caspase-3 in hippocampal neuron were detected by real-time PCR and western blot. Results Behavioral results showed that the swimming immobility time in depression model group, DHA group and combination group were respectively(113.33±9.50)s, (81.67±7.68)s and(73.00±8.54)s.Compared with depression model group, the DHA group and DHA combined with fluoxetine group obviously reduced the swimming immobility time of rats(t=8.164, 9.855, P<0.01). HE stain result showed DHA could partly recovered the number of hippocampal neurons in CA1, CA2 and CA3 and reduced apoptosis. qPCR and WB results showed DHA alone or DHA combined with fluoxetine could inhibit mRNA and protein level of caspase-3 in hippocampal neurons. Conclusion DHA can improve depression to a certain extent in a rat model of unforeseeable chronic stress depression, which might work through inhibition of neuron apoptosis and caspase-3 expression in hippocampal neurons. Key words: Docosahexaenoic acid; Depression; Hippocampal neuron; Apoptosis; Caspase-3