Abstract: Traditional Chinese medicines (TCMs) have demonstrated remarkable advantages in the clinical management of central nervous system (CNS) diseases. Understanding the material basis and mechanism of actions for the traditional Chinese medicines components has been actively pursued. Studies in the past years have generally tackled this issue from two aspects, including brain-centric investigations and systems-level researches guided by brain-body crosstalk. The two main lines of investigation have benefited from the application of integral omics and computational approaches in target discovery, as well as the progress from organ crosstalk studies. In this review, focusing on mechanistic studies of TCM in CNS disorders, we illustrate how advances in target identification and brain–body interaction research have contributed to understanding the material basis and neuropharmacology of TCMs. We also discuss the key issues in each direction and propose potential integral routes for further studies.