Nephrotic syndrome (NS) is a common nephropathy with a complex and diverse aetiology. Both Imperatae rhizoma and Hedyotis diffusa Willd. are herbs that are widely used as medicine and functional food. In traditional Chinese medicine theory, they are used as an herbal pair (HP) to treat inflammation-related diseases in the clinic, especially disorders of the kidney.This study aimed to investigate the anti-inflammatory and hypolipidaemic effects of HP in an NS rat model and provide scientific data for its clinical application.An NS model was established by two-dose injection of Sprague-Dawley rats with adriamycin. Seven groups, including the sham, model, HP treatment (0.25, 0.5 and 1.0 g/kg/d), prednisone (positive control, 5 mg/kg/d), and atorvastatin (positive control, 4 mg/kg/d) groups, were tested. The biochemical indexes of renal function and inflammatory cytokines were determined by ELISA kits and/or qPCR assays, and the crucial protein involved in the signalling pathway were subsequently tested by qPCR and/or Western blotting. Based on specific compounds identified by LC-Q-TOF-MS, network pharmacological study was carried out.The levels of BUN, Scr, Upro, UA, Alb, TC, TG, and LDL-C were significantly elevated in model rats. HP treatment for four weeks improved the renal function and the dyslipidaemia by decreasing the levels of all parameters, except BUN and Scr. HP treatment (0.5 and 1.0 g/kg/d) upregulated the expression of PPARγ, CYP7b1, and LDLR in the liver, while it down-regulated PCSK9, showing a regulatory effect on lipid metabolism disorder. The levels of TNF-α and IL-1β in the plasma and the mRNA expression of TNF-α, IL-1β, MCP-1, and TGF-β1 in the kidney were decreased in HP groups, revealing its anti-inflammatory effect in NS rats. The HP exerted an alleviation effect on the inflammatory response through the NF-κB pathway by inhibiting the mRNA and protein expression of p50 and p65. There were 34 compounds identified or tentatively characterized in HP. In the network pharmacological study, PPARG(PPARγ), PCSK9, RELA(p65), and NF-κB1(p50) were the top 20 targets for HP, supporting the animal experimental results.HP exhibited protective effects on NS rats. These effects might be closely related to the inhibition of NF-κB and PCSK9-LDLR and activation of the PPARγ-CYP7B1 signalling pathways.Copyright © 2021 Elsevier GmbH. All rights reserved.