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In our previous study, penta-acetyl geniposide ((AC)5GP) is suggested to induce tumor cell apoptosis through the specific activation of PKCδ. However, the downstream signal pathway of PKCδ has not yet been investigated. It was shown that JNK may play an important role in the regulation of apoptosis and could be a possible downstream signal of PKCδ isoforms. In the present study, we investigate whether JNK is involved in (AC)5GP induced apoptosis. The result reveals that (AC)5GP induces JNK activation and c-Jun phosphorylation thus stimulating the expression of Fas-L and Fas. Using SP600125 to block JNK activation shows that (AC)5GP-mediated apoptosis and related proteins expression are attenuated. Furthermore, we find that the (AC)5GP induces apoptosis through the activation of JNK/Jun/Fas L/Fas/caspase 8/caspase 3, a mitochondria-independent pathway. The JNK pathway is suggested to be the downstream signal of PKCδ, since rottlerin impedes (AC)5GP-induced JNK activation. Therefore, (AC)5GP mediates cell death via activation of PKCδ/JNK/FasL cascade signaling.