Traditional Chinese medicine (TCM) represents the crystallization of Chinese wisdom and civilization. It has been valued as the renewable source for the discovery of novel drugs, owing to its long-term proved efficacy in human diseases and abundant biologically active components pools. To dissect the mystery of TCM, modern technologies such as omics approaches (proteomics, genomics, metabolomics) and drug screening technologies (high through-put screening, high content screening and virtual screening) have been widely applied to either identify the drug target of TCM or identify the active component with certain bio-activity. The advent of high content screening technology has absolutely contributed to a breakthrough in compounds discovery and influenced the evolution of technology in screening field. The review introduces the concept and principle of high content screening, lists and compares the currently used HCS instruments, and summarizes the examples from ours and others research work which applied HCS in TCM-derived compounds screening. Meanwhile, this article also discusses the advantages and limitations of HSC technology in drug discovery from TCM libraries.