Cross-kingdom herbal miRNA was reported initially in 2012. Using a modified herbal extraction protocol, we obtained 73,677,287 sequences by RNA-seq from 245 plants used in traditional Chinese Medicine (TCM), of which 20,758,257 were unique sequences, including previously uncharacterized specimens. We constructed a Bencao (herbal) small RNA (sRNA) Atlas (http://bencao.bmicc.cn), annotated the sequences by sequence-based clustering, and created a nomenclature system for Bencao sRNAs. The profiles of 21,757 miRNAs in the Bencao sRNA Atlas were highly consistent with plant miRNAs in miRBase. Using software tools, our results demonstrated that all human genes might be regulated by small RNAs (sRNAs) from the Bencao sRNA Atlas, part of the predicted human target genes were experimentally validated. These results suggest that Bencao sRNA might be the main bioactive components of herbal medicines. We demonstrated roadmaps for RNA therapeutic development and optimization of TCM prescription. We propose a Bencao Index including nucleic acid (N), small-molecule compounds (SM), large-molecule compounds (LM), protein peptides (P) and elements (E) for quantitatively measuring medical effects of TCMs. The Bencao Index could be used to control the quality of different batches of TCMs and their patent medicines. The free and open Bencao small RNA Atlas is a resource to provide the scientific basis for herbal medicine’s mechanism of action and to accelerate the development of oligonucleotide drugs.