High fat diet (HFD) induced obesity plays a key role in onset of inflammation, a chronic response of the body to elevated expression of proinflammatory cytokines. Our work emphasized on assessing the therapeutic potency of the polyherbal formulations (PHF), composed of Phyllanthus urinaria and Adhatoda vascia nees by studying the expression pattern of iNOS, pro, anti-inflammatory cytokines, chemokine along with identification of potent anti-inflammatory compounds in HFD induced inflammation in four weeks old (23-25 g bw, n = 6 in triplcates) Swiss albino mice. The findings demonstrated high percentage of free radical scavenging property of PHF, downregulation of expression level of proinflammatory cytokines and chemokines, profound elevation of anti-inflammatory cytokines, anti-oxidant enzymes in both PHF treated groups signifying protection against oxidative stress. In silico study revealed binding energy of Okanin, Vomicine, Granisetron and Pisdic acid - 9.31 kcal/mol, - 8.34 kcal/mol, - 8.10 kcal/mol, - 7.93 kcal/mol respectively with strong protein ligand interaction with inflammatory, lipid marker PPARγ and insulin resistance marker protein receptor INSR. Among other four ligands, Peganine, Coralyne, Soraphen O and 2-hydroxyhexadecanoic acid; Soraphen O and Coralyne showed best binding affinity with INSR (- 6.8 kcal/mol) and PPARγ (- 6.9 kcal/mol) respectively. The evaluation based on network pharmacology, the active ingredients of the PHF for AMPK signalling pathway and protein analysis identified 121 targets. A network of interaction between the eight ligands and known therapeutic targets of INSR and AMPK depicted pharmacological mechanisms of the PHF in inhibition of insulin resistance by activating INSR and AMPK-pathway thus establishing itself as potent alternative drug in treating ailments associated with obesity induced inflammation.