Neuroinflammation is involved in the development of depression and may induce depression-like behaviors by affecting metabolism through interactions with circadian rhythms. As the hub of metabolism, mitochondria are regulated by various types of metabolism and release signals that regulate cellular functions. In this study, we performed transcriptomic analysis of the hippocampus of IL-33-overexpressing mice to provide new ideas to explore the pathogenesis of inflammation-mediated depression at the transcriptional level. Male C57BL/6J mice and IL-33-overexpressing mice were subjected to behavioral tests. The hippocampus was extracted during the light or dark period, and differential gene expression analysis was conducted using RNA sequencing. Differential gene enrichment analysis was performed, as well as multilayered analysis of mitochondrial transcriptional rhythms by integrating the regulatory networks and Mito 3.0 database. The results were further verified using RT-qPCR. IL-33-overexpressing mice exhibited depressive behaviors associated with rhythmic disorders and shortened circadian cycles. Differential KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis showed that the top 20 pathways with the lowest