Epigenetic disruption of tumor suppressor genes (TSGs), particularly DNA methylation, plays a key role in hepatocellular carcinoma (HCC) pathogenesis. Through methylome study, we identified BCLB as a methylated gene in HCC. BCLB was methylated in all tumor cell lines with silenced or reduced expression. BCLB was further found to be silenced in 55.2% (58/105) of HCC samples, while 91.4% (96/105) of paired non-tumor tissues showed high BCLB expression. BCLB protein expression was significantly correlated with HBV status (p = 0.036), AFP (p = 0.048), tumor size (p = 0.006), and TNM stage (p = 0.022). The overall survival and disease-free survival rate of HCC patients with positive BCLB expression were both significantly higher than those with negative BCLB expression (p = 0.032 and 0.027, respectively). Ectopic expression of BCLB in HCC cells inhibited cell growth in vitro and in vivo. Mechanistic study showed that BCLB expression was a starvation stress sensor inducing apoptosis and autophagy simultaneously in HCC cells through the adenosine monophosphate-activated protein kinase AMPK-mTOR signaling cascade. Thus, epigenetic suppression of BCLB expression is involved in HCC development, which might have therapeutic implications for HCC patients.