Endothelial cell protein C (EPCR), one of the main members in the protein C (PC) pathway, plays an important role in the process of coagulation and inflammation. EPCR can shed from the cell membrane, which process is mediated by the tumor necrosis factor-α converting enzyme (TACE) and related to some diseases. Andrographolide is the major constituent of Andrographis paniculata, a kind of herbal medicine commonly used in clinical for its various pharmacological actions, especially anti-inflammation and anti-cancer. In this study, we investigated andrographolide protection for EPCR and its potential molecular mechanism. Phorbol-12-myristate-13-acetate (PMA)-stimulated human umbilical vein endothelial cells (HUVECs) were used to be the model of EPCR shedding and the andrographolide pretreatment was tested in this model. The results showed that andrographolide could reduce PMA-induced EPCR shedding and inhibit the TACE function. Additionally, we found andrographolide also suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38, but had no effect on extracellular regulated protein kinase (ERK) 1/2. Given these results, andrographolide can inhibit the shedding of EPCR by the suppression of TACE, which may take JNK and p38 as the molecular target. These findings indicated a substantial anti-EPCR shedding efficacy of andrographolide in vitro.