Kruppel-like family (KLF) members are important regulators of proinflammatory activation in the vasculature. A transcriptome study involving RNA sequencing (RNA-seq) and quantitative PCR (qPCR) was performed to investigate Klf15 and Klf15-regulated gene levels in C57BL/6 mice with inferior vena cava thrombi and in control (Blank) mice. A total of 2,206 differentially expressed genes (DEGs), including 1,330 upregulated and 876 downregulated genes, were identified between the deep venous thrombosis (DVT) group and the Blank group. Additionally, 1,041 DEGs (235 upregulated and 806 downregulated) were identified between the Klf15-small interfering RNA (siRNA) and Klf15-negative control (NC) groups. The DEGs were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and qPCR was conducted to validate the results. A total of seven significant DEGs were selected from the RNA-seq results. Matrix metalloproteinases (Mmp)12, Mmp13, Mmp19, Arg1, Ccl2, heme oxygenase-1 and Fmo3 levels were significantly higher, while Klf15 levels were lower, in the DVT group than in the Blank group. Fmo3 and Mmp19 have not been previously identified as DVT-associated DEGs. Klf15, Mmp12 and Mmp13 levels were compared between the Klf15-siRNA and Klf15-NC groups. Mmp12 and Mmp13 expression was significantly higher, while that of Klf15 was lower, in the Klf15-siRNA group than in the Klf15-NC group. Critical roles of Klf15, Mmp12 and Mmp13 have been identified, which have not previously been shown to help regulate DVT initiation and progression. Moreover, Klf15-mediated regulation of DVT may be modulated by downregulation of various genes, such as Mmp12 and Mmp13, potentially providing a theoretical foundation and diagnostic criteria for DVT treatment.