<p>This study investigates the therapeutic potential of <i>Ailanthus excelsa</i> (AE) in managing obesity and metabolic disorders by targeting lipid-sensing nuclear receptors, particularly PPAR-α/β/δ/γ. The hydroalcoholic extract of <i>Ailanthus excelsa</i>, obtained through ultrasonic-assisted extraction, was analyzed using a systems biology approach and in vitro studies. The in vitro evaluation included cytotoxicity assessment and cellular uptake in 3T3-L1 cells, along with glucose uptake studies in L6 muscle cells, HepG2 liver cells, and 3T3-L1 adipocytes. A network pharmacology analysis identified several bioactive compounds quinic acid, methyl gallate, caftaric acid, and vitexin, and their interaction with PPAR, PI3K-Akt, AMPK, and insulin signaling pathways. Molecular docking studies were conducted to assess the binding of caftaric acid to PPAR receptors, and molecular dynamics simulations evaluated binding stability and energy profiles. In vitro studies revealed no cytotoxicity of the hydroalcoholic extract. The extract demonstrated antioxidant and membrane-protective effects through anti-hemolytic activity [61.93 ± 2.39]. Glucose uptake assay was carried out on L6 cell line (skeletal muscles) and 3T3L1 cell lines (adipose tissue) which demonstrate 67.06% and 73.89% of glucose uptake respectively. Similarly, HepG2 (liver cells) were used to mimic the effect of <i>Ailanthus excelsa</i> on GLUT2 carriers, that demonstrated 71.05% of glucose uptake as compared to insulin (91.13%). cellular uptake assay shows AE exhibited the highest cellular uptake (115.82%) compared to the control (81.27%), suggesting enhanced internalization efficiency. The study highlights <i>Ailanthus excelsa’s</i> lipid-modulating potential through the regulation of PPAR and PI3K-Akt signaling pathways, supporting its therapeutic use in managing obesity and metabolic disorders. </p> Graphical abstract <p></p>