Over the past decade, natural compounds have been proven to be effective against many human diseases, including cancers. Triptolide (TPL), a diterpenoid triepoxide from the Chinese herb Tripterygium wilfordii Hook F, has exhibited attractive cytotoxic activity on several cancer cells. An increasing number of studies have emphasized the antitumor effects of TPL on non-small cell lung cancer (NSCLC). Here we mainly focused on the key molecular signaling pathways that lead to the inhibitory effects of TPL on human NSCLC, such as mitogen-activated protein kinases (MAPKs) modulation, inhibition of NF-κB activation, suppression of miRNA expression, etc. In addition, the effect of TIG on immune response in cancer patients is summarized for improved immune modulation utilization. However, the clinical use of TPL is often limited by its severe toxicity and water insolubility. Future clinical trials and drug delivery strategies that will evaluate the security and validate the underlying tumor-killing properties of TPL in human NSCLC are also to be discussed.