Background: Severe burns are a leading cause of injuries worldwide and are usually accompanied by considerable morbidity and mortality. The purpose of this study was to investigate the changes of gene expression in blood and skin at different times after severe burn.Methods: Firstly, the gene expression profiles of different burn time samples in GSE19743 and GSE8056 were analyzed. Secondly, the maladjusted gene network was identified by protein-protein interaction (PPI) network, and the genes in the network were enriched and analyzed. In addition, the key dysfunctional genes were identified by betweenness algorithm, and evaluated by survival analysis, Cox analysis, receiver operating characteristic (ROC) analysis. Finally, crosstalk analysis and enrichment analysis were carried out between the blood-and skin-specific differentially expressed genes (DEGs) at different burn times. Results:The results showed that there were common DEGs in the blood and skin at different burn times.Importantly, we screened out the key dysfunctional genes BIRC5, NCAM1, PCNA, TOP2A, and VEGFA, which were related to the course of burns. Enrichment analysis showed that these maladjusted genes were mainly involved in the immune inflammation-related signal pathway. Additionally, significant crosstalk was identified between blood-and skin-specific genes at different burn times, especially in the blood. The signal pathways involved in specific genes represent their own pathological characteristics.Conclusions: Both blood and skin tissues express common pathological changes and unique molecular mechanisms at different times after burn injury. The results of this study provide guidance for clinical personalized treatment.