Signal transducer and activator of transcription 3 (STAT3) plays pivotal role in several cellular processes such as cell proliferation and survival and has been found to be aberrantly activated in many cancers. STAT3 is largely believed to be one of the key oncogenes and crucial therapeutic targets. Much research has suggested the leading mechanisms for regulating the STAT3 pathway and its role in promoting tumorigenesis. Therefore, intensive efforts have been devoted to develop potent STAT3 inhibitors and several of them are currently undergoing clinical trials. Nevertheless, many natural products were identified as STAT3 inhibitors but attract less attention compared to the small molecule counterpart. In this review, the development of natural STAT3 inhibitors with an emphasis on their biological profile and chemical synthesis are detailed. The current state of STAT3 inhibitors and the future directions and opportunities for STAT3 inhibitor are discussed.