Morphinone (MO) is an electrophilic metabolite of morphine. Electrophiles can modify thiol groups of proteins, resulting in the activation of redox signaling pathways and toxicity. We have previously reported that the atmospheric electrophile, 1,4-naphthoquinone, and electrophilic organometallic compound, methylmercury, activate protein kinase B (Akt) signaling through modification of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), which is a negative regulator of Akt. In the present study, we examined whether MO activates Akt signaling. Exposure of HepG2 cells to MO enhanced translocation of Akt to the nucleus in a concentration-dependent manner. MO phosphorylated Akt and its downstream protein, cAMP response element-binding protein (CREB), and upregulated B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein. An analogue of MO dihydromorphinone that was not electrophilic did not enhance the phosphorylation of Akt and CREB or expression of Bcl-2, suggesting the importance of electrophilicity of MO in activation of the cascade. Pretreatment of the cells with wortmannin suppressed MO-mediated phosphorylation of Akt and CREB and expression of Bcl-2, and enhanced MO-induced cytotoxicity, indicating that MO activates Akt–CREB–Bcl-2 signaling in HepG2 cells. This signaling pathway might be capable of modulating MO-mediated toxicity in cells.