Here, we compared the modulatory effects of different dose levels of Uxi (Endopleura uchi aqueous bark extract, EUAE) vs simvastatin (SIM) on hyperlipidemia, metabolic stress, and liver dysfunction in HFD-induced obese rats. HFD significantly increased BMI, lee index, body adipose index, atherogenic indices, cellular toxicity markers, blood glucose level, adipokines, pro-inflammatory mediators, lipid peroxidation and promoted lipid accumulation and HMGCR and ACC. Furthermore, it significantly decreased antioxidants, ghrelin, and AG/UAG ratio as well as hepatic glycogen content, while these changes were mitigated by either SIM or EUAE treatment. The expression of FASN & SREBP1c genes were elevated in the HFD group, with downregulation of PPARα expression. These alterations were ameliorated by SIM or EUAE treatment. The beneficial effects of EUAE may be attributed to its phenolic compounds and their derivatives. This study supports the hypothesis that Uxi may have antihyperlipidemic, antioxidant, hepatoprotective, and anti-inflammatory properties in rat model of obesity.