Natural bud sports can lead to the development of plants with unique phenotypic traits such as changes in color, size, or disease resistance. In this report, biochemical, transcriptomic, and genomic analyses were conducted on a natural bud sport of the ‘Flame’ grapefruit compared to its wild-type genotype in response to Huanglongbing (HLB; Citrus greening) disease. The biochemical analysis of the bud sport genotype leaves revealed an increase in chlorophyll content and a decrease in starch accumulation compared to the wild-type genotype. Transcriptomic analysis identified significant differences between the bud sport and wild-type genotypes, with 738 genes being upregulated and 3899 genes downregulated. Differential expression of genes encoding for phloem proteins, phytohormones such as jasmonic acid and gibberellic acid, pathogenesis-related (PR) genes, and their negative regulators were observed in this study. Callose deposition-related genes were downregulated in the bud sport, suggesting that the bud sport ‘Flame’ grapefruit might modulate phloem genes in response to Candidatus Liberibacter asiaticus (CaLas) without excessive callose deposition. Overexpression of WRKY transcripts involved in pathogenesis-related (PR) gene expression, such as the NIM1 interacting 1 transcript, suggests activation of PR-mediated defense. Downregulation of carbohydrate metabolism and several major transporter transcripts may be responsible for resource allocation strategies to limit bacterial spread. Altered expression of some of the key genes and pathways in the bud sport produced a better response to CaLas than the wild-type following HLB infection, indicating that the bud sport may be modulating its defense strategies to cope against the pathogen. The SNP polymorphism identified through genotyping-by-sequencing determined meaningful genetic distinction between bud sport and wild-type genotypes derived from the same plant, facilitating precise genetic characterization and analysis.