ABSTRACT Obesity-related health problems are worsening in various societies worldwide. Artemisia anuua L. (AA) has distinctive health benefits, including anti-inflammatory, antioxidant, and insulin-sensitizing properties. Nanoformulation of herbal extracts is a new approach to enhance the bioavailability of natural products. This study aimed to evaluate the efficacy of AA extract, either the conventional extract (AAE) or its nano-form (AAEN), in modulating obesity-related metabolic complications in hypercaloric (high-fat/high-sucrose) diet-induced obese rats. Forty-eight rats were divided into two groups fed either a basal or hypercaloric diet for twelve weeks. Starting from the eighth week, each main group was subdivided into three subgroups and treated orally with either saline, AAE, or AAEN until the end of the experiment. Both AAE and AAEN exerted antiadipogenic effects. They reduced body weight and epididymal fat, mitigated dyslipidemia, improved glucose utilization and insulin resistance, reduced hyperleptinemia, increased serum adiponectin, and decreased oxidative stress and inflammatory markers. These results were mediated by regulating SIRT-1, PGC-1α, SREBP-1, PPAR-γ, FAS, LPL, IRS 1, and GLUT4 gene expression, suggesting an effect of AA on de novo lipogenesis and glucose utilization. The AAEN produced more expressive ameliorating effects than the conventional extract. AAE administration ameliorated the obesity-associated metabolic complications induced by feeding a hypercaloric diet, implying that this extract may be used as a complementary treatment option for obesity and its metabolic consequences. The antiadipogenic effectiveness of AAE was enhanced by its nanoformulation, suggesting that the nanoparticle system can be applied to boost other herbal medicine effectiveness.