Silicosis is a long-established public health issue in developing countries due to increasingly serious air pollution and poorly implemented occupational safety regulation. Inhalation of silica triggers cytotoxicity, oxidative stress, pulmonary inflammation and eventually silicosis. Current understanding in the pathogenesis and mechanism of silicosis is limited, and no effective cure is clinically available once silicosis is developed. A number of studies were conducted to investigate silica-induced alternate gene expressions in pulmonary cells. However, transcriptome analysis in a silicosis animal model is needed. This study was performed to evaluate the transcriptional alternations in silicotic mice using comparative RNA-Seq. A silicosis mice model was established by intratracheal instillation of silica suspensions, and validated by histological examinations. High-throughput sequencing and differential gene expression analysis revealed 749 upregulated genes and 70 downregulated genes in the silicosis model. Genes related to immune cell interactions, immune cell responses and inflammation were significantly enriched. Cytokine-cytokine receptor interaction and downstream JAK-STAT signaling pathways were the most significantly enriched KEGG pathways. Reverse transcription-polymerase chain reaction analysis and immunohistochemistry were performed to validate further the differential expression patterns of representative genes. The reported results in this study provide the basis for elucidating the molecular mechanisms for silica-induced pulmonary inflammation and fibrosis, and support the prevention and treatment of silicosis.