Objective To observe the effects of fluoxetine on the behavior in rats of ischemic post-stroke depression (PSD) and the influence on neurogenesis in the hippocampus. Methods Thirty-two adult male Sprague-Dawley rats were randomly divided into control, stroke, PSD, and fluoxetine groups (n = 8 each). Complete cerebral ischemic rat models were established by left middle cerebral artery occlusion. Chronic unpredictable mild stimulation(CMUS) and an isolation feed were used to establish the rat depression model. Changes in rat behavior were evaluated by a sucrose preference test, open field test, and weight changes on days 0, 7, 14, 21, 28, and 35 after the operation.A forced swim test was performed on day 35, and then all rats were sacrificed to detect neuron regeneration in the hippocampus by immunohistochemical staining. Results The rat body weight, sucrose preference test, and horizontal and vertical movement scores in the open field test on days 28 and 35 after CMUS were measured. The differences in the PSD group compared with stroke and fluoxetine prevention groups had statistical significance ( P <0. 05). Compared with the stroke group, in the forced swim test, the immobility time of rats was increased in the PSD group ( P < 0. 01), and the swimming and climbing times were decreased ( P < 0. 01). However, immobility and swimming times were improved after fluoxetine treatment ( P < 0. 01). Immunohistochemical staining showed that, compared with the stroke group, the number of new neurons in the hippocampal dentate gyrus of rats was significantly reduced in the PSD group ( P < 0. 01), but compared with the PSD group, it was increased in the fluoxetine-treated rats ( P < 0. 01). Conclusions Fluoxetine may effectively improve PSD rat depression behavior, and hippocampal neurogenesis plays an important role in this process.