Abstract Fire blight of pear is caused by Erwinia amylovora, which can cause devastating damage to pear trees and other pome fruit trees worldwide. Fire blight has resulted in a reduction in the production of Korla fragrant pears in Xinjiang, China, as well as a decrease in their quality and taste, causing severe economic losses. To this end, a comparative transcriptome analysis of common Korla fragrant pear (KFP, susceptible) and a bud mutation line (1910, resistant) at three inoculation periods was conducted. Clustering and principal component analysis (PCA) of the RNA-seq data revealed that the differences between lines were greater than those within lines. A total of 7271 DEGs were identified in the bud mutation line, while 11,937 DEGs were identified in KFP. Between KFP and the resistant material bud mutation line, 11,937 DEGs were identified, which were significantly enriched in the pathways of photosynthesis, jasmonic acid metabolic process, flavonoid biosynthesis, and starch and sucrose metabolism. A total of 8 clusters were identified for all (17,354) DEGs via k-means, and KEGG pathway annotations were performed for each individual cluster. In addition, the 1027 differentially expressed transcription factors (TFs) were clustered into five clusters, and the TFs with the largest fold change in each cluster were identified. A gene coexpression network was further constructed through weighted correlation network analysis (WGCNA), and 15 key genes that determine the fire blight resistance of Korla fragrant pear were identified. These research results provide a theoretical basis for a deeper understanding of the molecular mechanism of Korla fragrant pear resistance to fire blight and provide new genetic resources for the study of Korla fragrant pear resistance to fire blight.