Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases without effective pharmacological intervention. Liensinine (LIEN), a plant-derived isoquinoline alkaloid, exerts key roles in regulating various cellular processes. However, its potential on NAFLD progression has not been reported. In the study, we attempted to explore the regulatory effects of LIEN on fatty liver, and the underlying molecular mechanisms. Our in vitro experiments showed that LIEN treatments significantly reduced the lipid deposition in palmitate acid (PA)-treated cells by improving AMP-activated protein kinase (AMPK) activation. Additionally, excessive reactive oxygen species (ROS) generation was also strongly down-regulated by LIEN in cells upon PA stimulation through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. Moreover, PA triggered inflammatory response was markedly restrained by LIEN via the blockage of TGF-8-activating kinase 1/nuclear factor-kappa B (TAK1/NF-kappa B) signaling. Intriguingly, we further found that LIEN-prohibited ROS production, lipid disorder and inflammation were largely dependent on AMPK activation through repressing TAK1. Consistently, our in vivo experiments confirmed that LIEN treatments efficiently improved the metabolic disorder, insulin resistance, dyslipidemia in high fat diet (HFD)-fed mice. Furthermore, HFD-triggered oxidative stress and inflammation in liver were greatly meliorated by LIEN administration by mediating Nrf2 and TAK1 signaling pathways, respectively. Collectively, all these findings demonstrated that LIEN exerted anti-dyslipidemia, antioxidant and anti-inflammatory effects to alleviate NAFLD progression mainly through modulating TAK1/AMPK signaling, and thus could be considered as a promising therapeutic strategy.