Tamoxifen is a clinical drug for estrogen receptor (ER)-positive breast cancer. Recently, it has been detected in aquatic environment. The residual drugs will produce certain biological activity and create a risk to aquatic organism when they enter the water environment. Therefore, it has great significance to study the ecotoxicity of tamoxifen. In the study, we used zebrafish as a model of aquatic to investigate the ecotoxic mechanism of tamoxifen to aquatic. We found that tamoxifen induced liver lipid accumulation in zebrafish, which showed a significant hepatotoxicity with smaller liver area and bigger yolk area. Though biochemical and pathologic measurement, tamoxifen treated group showed higher transaminase and lipid content. The elevated liver lipid synthesis might due to the increase of lipid metabolism related gene Srebf1, Srebf2 and Fasn. Moreover, inflammatory cytokine Tnf-α, Il-1β And Il-6 were increased. This result confirmed the toxicity of tamoxifen to aquatic, suggested liver injury was the main characteristic of its ecotoxicity. This study indicated it is important to avoid tamoxifen discharging into the aquatic ecology and provided a theoretical basis of prevention tamoxifen-induced ecotoxicity to aquatic.