Medication therapy seems to be an effective treatment for major depressive disorder (MDD). However, although the efficacies of various medicines are equal or similar on average, they vary widely among individuals. Therefore, an understanding of methods for the timely evaluation of short-term therapeutic response and prediction of symptom improvement after a specific course of medication at the individual level at the initial stage of treatment is very important. In our present study, we sought to identify a neurobiological signature of the response to short-term antidepressant treatment. Related brain network analysis was applied in resting-state electroencephalogram (EEG) datasets from patients with MDD. The corresponding EEG networks were constructed accordingly and then quantitatively measured to predict the efficacy after eight weeks of medication, as well as to distinguish the therapeutic responders from non-responders. The results of our present study revealed that the corresponding resting-state EEG networks became significantly weaker after one week of treatment, and the eventual medication efficacy was reliably predicted using the changes in those network properties within the one-week medication regimen. Moreover, the corresponding resting-state networks at baseline were also proven to precisely distinguish those responders from other individuals with an accuracy of 96.67% when using the spatial network topologies as the discriminative features. These findings consistently provide a deeper neurobiological understanding of antidepressant treatment and a reliable and quantitative approach for personalized treatment of MDD.