Hyperlipidemia, a common metabolic disease, is a risk factor for cardiovascular diseases, Poria cocos (PC) and Alismatis rhizoma (AR) serve as a potential treatment. A systematic approach based on transcriptome sequencing analysis and bioinformatics methods was developed to explore the synergistic effects of PC–AR and identify major compounds and potential targets. The phenotypic characteristics results indicated that the high dose (4.54 g/kg) of PC–AR reduced total cholesterol (TC), elevated high-density lipoprotein cholesterol (HDL-C) levels, and improved hepatocyte morphology, as assessed via hematoxylin and eosin (H&E) staining. Transcriptomic profiling processing results combined with GO enrichment analysis to identify the overlapping genes were associated with inflammatory responses. The cytokine-cytokine receptor interaction pathway was found as a potential key pathway using geneset enrichment analysis. Core enrichment targets were selected according to the PC–AR's fold change versus the model. Real-time quantitative PCR analysis validated that PC–AR significantly downregulated the expression of Cxcl10, Ccl2, Ccl4, Cd40 and Il-1β mRNA (P < 0.05). Molecular docking analysis revealed the significant compounds of PC–AR and the potential binding patterns of the critical compounds and targets. This study provides further evidence that the therapeutic effects of PC–AR on hyperlipidemia in rats through the regulation of inflammation-related targets.