The liver has an elegant regenerative capacity. After mild liver injury, hepatocytes proliferate to restore the lost liver mass and function. However, when hepatocyte proliferation is impaired, which occurs upon severe liver injury or in chronic liver diseases, biliary epithelial cells (BECs) activate and give rise to hepatocytes. The only effective therapy for patients with severe chronic liver diseases is liver transplantation, but the shortage of donor livers necessitates alternative therapies. Studying BEC-driven liver regeneration may provide insights into how to augment innate liver regeneration in the liver patients as the alternative therapy. Here, we presented a new liver regeneration model in which BECs contribute to regenerated hepatocytes upon hepatocyte damage and loss. The hepatocyte damage results from temporary knockdown of the mitochondrial import gene tomm22 by morpholino antisense oligonucleotides (MO) as reported by Curado et al., 2010. We found that all hepatocytes in tomm22 MO-injected larvae at 7 days post-fertilization (dpf) weakly expressed Tp1:H2B-mCherry, a BEC marker, suggesting BEC origin of these hepatocytes. To unequivocally determine the origin of the regenerated hepatocytes, we permanently labeled BECs with a BEC Cre line, Tg(Tp1:CreERT2), and traced their lineage in the MO-injected larvae. Surprisingly, we found maximum 60% of the hepatocytes were derived from BECs, suggesting that both BECs and survived, pre-existing hepatocytes contribute to the regenerated hepatocytes in the MO-injected larvae. In addition, we found that in the MO-injected larvae, survived hepatocytes weakly induced Tp1:H2B-mCherry expression, suggesting hepatocyte dedifferentiation. Furthermore, we found that both macrophage ablation and the suppression of Wnt/β-catenin signaling in the MO-injected larvae increased the number of Tp1:H2B-mCherry-negative hepatocytes and concomitantly decreased the number of Tp1:H2B-mCherry-positive hepatocytes at 7 dpf. This new liver regeneration model will help one better understand the mechanisms of liver regeneration upon hepatocyte damage and loss.