Objective To select the optimal acupoints formula by evaluating the efficacy of different groups of acupoints in the treatment of post-stroke depression (PSD) with acupuncture. Method Totally 108 PSD patients were randomized into 3 groups, i.e. Neiguan (PC6) group, Taichong (LR3) group, and Baihui (GV20) group, 36 cases each. The acupuncture treatment was given once a day, 5 sessions a week, 3 weeks as a treatment course. The clinical efficacies were compared among the 3 groups after the intervention. The 3 groups were evaluated by the Hamilton Depression Scale (HAMD), National Institute of Health Stroke Scale (NIHSS), and Quality of Life Scale (QOL) before and after the treatment, and the results were statistically analyzed. Result The effective rates were respectively 72.2%, 75.0%, and 86.1%in Neiguan group, Taichong group, and Baihui group, and the inter-group differences were statistically significant (P<0.05); the HAMD, NIHSS, and QOL scores were significantly changed after the intervention in the 3 groups (P<0.01);the inter-group differences in the NIHSS and QOL scores were statistically insignificant (P>0.05). Conclusion The three groups of acupoints are effective in improving the depression symptoms, neural defect and QOL, while Baihui group can produce a more significant efficacy in improving the depression symptoms compared to Neiguan and Taichong groups;the effects in improving neural defect and QOL are equivalent among the 3 groups of acupoints.