BACKGROUND: Huanglongbing (HLB) is a devastating bacterial disease caused by the bacterium Candidatus Liberibacter asiaticus (CaLas) that affects the citrus industry worldwide. This study investigated the response of two pummelo x finger lime hybrid siblings to natural infection with CaLas. The hybrids were identified primarily using leaf morphology and molecular marker assessments and were selected for further studies on the basis of the CaLas titers in leaf petioles. RESULTS: HLB-infected budwood from the selected hybrids (PFL 2-61 and PFL 1-11), as well as the two parental plants, were propagated by grafting onto Swingle citrumelo rootstocks for further evaluation. Plant samples were collected two years after grafting for analysis. Leaves of PFL2-61 exhibited decreased CaLas titers compared with those of PFL 1-11. Additionally, we recorded increased chlorophyll content, total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity in PFL 2-61 compared to PFL 1-11 and the parents. We subsequently conducted a detailed investigation of these two hybrid siblings using transcriptome analysis. Among the 20,675 differentially expressed genes (DEGs) identified, 1,416 were downregulated in PFL 2-61 compared with PFL 1-11, whereas 326 were upregulated. Transcriptome analysis revealed that many of the DEGs were associated with the cell wall structure, redox homeostasis, and biotic stress responses. Moreover, key genes related to the biosynthesis of secondary metabolites and phytohormones, including PAL1, jasmonate-related genes, and WRKY transcription factors, were upregulated in the tolerant hybrid (PFL 2-61). In contrast, three transcripts associated with the Sieve Element Occlusion N-Terminus (SEO_N) domain were downregulated in the tolerant hybrid (PFL 2-61). CONCLUSIONS: Our findings provide valuable insights into the molecular mechanisms of tolerance and susceptibility to HLB in finger lime derived hybrids, highlighting the potential of this citrus species towards developing disease-tolerant varieties.