Abstract The aim of this study was to assess the therapeutic efficacy of the serotonin norepinephrine reuptake inhibitor (SNRI), milnacipran, on both cognitive impairment and depression in post-stroke depression (PSD) patients. A total of 18 PSD patients, approximately 3 months after stroke, were divided into two groups, milnacipran and control. A total of 10 patients were assigned to the milnaciprane group and eight were assigned to control group. Their cognitive impairment and mood symptoms were measured using the Mini-Mental State Examination (MMSE) and Hamilton Depression Rating Scale (HAM-D) both at the time of admission and at discharge, an interval of approximately 3 months. This study examined the changes in both MMSE and HAM-D scores during the study period. A significant time-by-group interaction for results of the MMSE was observed, although there was no significant difference between the two groups on the HAM-D. Amelioration of cognitive impairment was greater in the milnacipran group than the control group. For PSD patients, milnacipran is effective in improving cognitive dysfunction.