Lupus nephritis (LN) is one of the principal causes of mortality and disability in patients with systemic lupus erythematosus. Sirolimus has been used to treat patients with LN; however, the effects and mechanism of sirolimus in these patients remains unclear. The present study aimed to elucidate the therapeutic effects and mechanisms of sirolimus in LN mice using low, medium and high doses of sirolimus (0.1, 0.3 and 1 mg/kg, respectively). The survival probability and kidney index were calculated, and renal fibrosis was determined using Masson's Trichrome staining. The expression levels of E‑cadherin, α‑smooth muscle actin (α‑SMA) and vimentin were assessed via immunofluorescence analysis. Transcriptome analysis of control and sirolimus‑treated LN mice was performed using RNA‑sequencing, differentially expressed gene (DEG) identification and annotation, and Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The results suggested that a medium dose of sirolimus alleviated renal fibrosis and increased the survival rates of mice with LN (P<0.05). Furthermore, transcriptome analysis revealed 334 DEGs associated with LN, 176 of which were upregulated and 158 were downregulated. Following GO functional enrichment, 'biological process', 'molecular function' and 'cellular component' terms were identified. A total of 10 KEGG pathways were enriched, with 'cytokine‑cytokine receptor interaction' and 'interleukin‑17 signaling pathway' being significantly enriched (P<0.05). To the best of our knowledge, the present study is the first to conduct transcriptome analysis of LN mice treated with sirolimus, and demonstrated that a dose of 0.3 mg/kg exerted the greatest therapeutic effects.