As an essential component of the innate immune system, Toll-like receptors (TLRs) are a family of well-recognized ligand-binding receptors found in various organisms and initiate host immune responses. Activation of TLRs signaling pathways lead to the induction of numerous genes that function in host defense. Baicalin is a natural compound from the dry raw root of Scutellaria baicalensis (S. baicalensis) and it has been found to exhibit several pharmaceutical actions, such as anti-inflammation, anti-tumor and antivirus. These biological activities are mainly related to the regulatory effect of baicalin on the host immune response. In this review, we provide an overview of the regulation of baicalin on TLRs signaling pathways in various pathological conditions, and highlight potential targets for the development of the regulatory effect of natural compound from traditional Chinese medicine on innate immune system.