Objective To understand some key genes and metabolic/inflammatory pathways triggered by high fat/high cholesterol (HF/HC) diet-induced hyperlipidemia in Mongolian gerbil. Methods Sixty 90-day-old Mongolian gerbils (including both sexes) were used in this study. The gerbils were divided into normal group (n=30, control diets) and model group (n=30, Hf/HC diets). Hyperlipidemia was induced for 4 weeks. To extract mRNA for transcriptome by RNA-Seq deep sequencing and bioinformatics. Results The results showed that 47 522 de novo gerbil genes (≥100 bp unigene) were obtained, with a total of 26.9 Mb, and about 82.53% sequence was homologous with the exon in the common genome bases. There were 21 125 differential genes between the hyperlipidemia gerbil and normal gerbil groups, including 16 087 down-regulated and 5038 up-regulated genes. There was a significant trend of downregulation compared with the normal group (P<0.01). There were eight pathways significantly related to the metabolic inflammation in hyperlipidemia (P<0.01), and among the expressed genes of these pathways, 15 immune-and inflammation-related genes were significantly down-regulated (P<0.01). Conclusions RNA-Seq and bioinformatics techniques can be used as a powerful tool for overall gene-transcription in hyperlipidemic gerbil models. Some key genes and pathways screened in this study may become candidate genes or operating targets in the future research.