Objective To construct and evaluate a mouse model of renal fibrosis (RF) combined with Qi deficiency and dampness stasis, and investigate the changes in protein and metabolic pathways using multiomics. Methods Twenty-four C57BL/6J mice were divided randomly into normal (N), model (M), and RF and syndrome combined groups (BZ) (n=8/group). The experiment lasted 6 weeks. A mouse model of RF with Qi deficiency and dampness stasis was established by “cyclosporine A+high-fat diet+swimming exhaustion+constant temperature and humidity”. The model was evaluated by detecting general signs, renal function, tongue RGB (red, green, blue) values, hemorheology indexes, blood lipids, and inflammation and oxidation indexes, combined with hematoxylin and eosin, Masson, periodic acid-Schiff, and Oil red O staining, terminal deoxynucleotidyl transferase dUTP nick end labeling apoptosis, and transforming growth factor-β immunofluorescence analysis of renal tissue. Differential proteins and metabolites were screened by renal proteomics combined with serum metabolomics and subjected to pathway enrichment analysis. Results Body mass of mice in the BZ group began to decline at week 3 (P<0.05) and decreased significantly at week 4 (P<0.01), while food and water consumption decreased, the fur became messy and less glossy, mood and activity decreased, and stools became watery. Serum creatinine, blood urea nitrogen, urine albumin-creatinine ratio, and N-acetyl-beta-glucosaminidase (NAG) were significantly higher in the BZ group compared with those in the N group (P<0.05, P<0.01), and serum creatinine and NAG levels were significantly different compared with those in the M group. The R value of tongue images was significantly lower in the BZ group compared with that in the N group (P<0.01), while the B value was significantly higher (P<0.05). The viscosity of the whole blood multi-shear rate and the hematocrit were higher in the BZ group compared with those in the N and M groups, and the platelet volume was higher than in the N group (P<0.05, P<0.01). Total cholesterol, low-density lipoprotein cholesterol, C-reactive protein, interleukin-6, and malondialdehyde levels were significantly increased in the BZ group compared with those in the N and M groups (P<0.01), and superoxide dismutase activity was significantly decreased compared with that in the N group (P<0.05). Renal tubule vacuolation, inflammatory cell infiltration, glomerular basement membrane thickening, collagen fiber hyperplasia, and lipid accumulation were evident, and renal cell apoptosis and transforming growth factor-β deposition were increased in the BZ group. There were 299 differential proteins in the BZ and N groups, including 180 up-regulated and 119 down-regulated proteins, and 323 differential metabolites, including 205 up-regulated and 118 down-regulated. Primary bile acid biosynthesis, taurine and hypotaurine metabolism, and biosynthesis of unsaturated fatty acids were co-enriched in differential proteins and differential metabolites, involving three differential proteins and nine differential metabolites. Among these, docosapentaenoic acid (22n-3), eicosapentaenoic acid, taurine, 3-sulfinoalanine, taurocholic acid, Acnat1, Acnat2, and Hsd17b12 showed high prediction accuracy. Conclusions We successfully constructed an RF animal model of Qi deficiency and dampness stasis using the “cyclosporine A +high-fat diet+exhaustion of swimming+constant temperature and humidity” method. Biosynthesis of unsaturated fatty acids and taurine and hypotaurine metabolism may play important roles in this RF mouse model of Qi deficiency and dampness stasis.