Oridonin, the main active component of Rabdosia rubescens, has antitumor activities in experimental and clinical settings. The aims of the current study were to explore the anticancer abilities of oridonin in hepatoblastoma (HB) HuH-6 cells and to investigate the underlying mechanisms. We found that oridonin inhibited HuH-6 cell in vitro growth in a dose- and time-dependent manner. Further, oridonin induced HuH-6 cell apoptosis and G2/M cell cycle arrest. Upon studying the mechanism, we found that oridonin treatment caused endoplasmic reticulum (ER) stress activation. Meanwhile, ER stress inhibitor salubrinal- or inositol-requiring enzyme 1 (IRE-1) shRNA silencing inhibited oridonin's anti-HuH-6 effects, while ER stress inducers thapsigargin (Tg) and tunicamycin (Tm) mimicked oridonin's actions on HuH-6 cells. Oridonin also activated apoptosis signal regulating kinase 1 (ASK1)-c-Jun N-terminal kinase 1 (JNK1) signaling in cultured HuH-6 cells, which was inhibited by IRE-1 silencing. Importantly, the JNK inhibitors suppressed oridonin-induced growth inhibition and apoptosis in HuH-6 cells. In conclusion, our results suggest that oridonin induces growth inhibition and apoptosis in cultured HuH-6 cells involving ER stress and ASK1/JNK signaling pathways, which enhances our understanding of the molecular mechanisms of oridonin in HB management.