Citrus is the prime fruit crop cultivated worldwide, and well known for nutritional, organoleptic and nutraceutical related properties. Citrus fruits are rich source of several secondary metabolites (SM), like flavonoids, ascorbic acid, polyphenols, carotenoids, terpenoids, and limonoids. Citrus have evolved a multitude of defense mechanisms to enhance their resilience against biotic and abiotic stresses, with SM playing a critically significant role in plant survival, defence, adaptability, and reproduction. Among all biotic stresses, Huanglongbing (HLB, citrus greening) is the major constraint to limits citrus production. HLB is a destructive disease caused by Candidatus Liberibacter spp. HLB has been found in nearly all cultivated varieties which causes the losses by affecting fruit development, quality, tree vigor, and production. This review gives brief highlights on these compounds and discussed their function in citrus defence mechanism, role in fruit maturation, metabolic responses against Huanglongbing (HLB), and hormone signalling pathways. Majority of the amino acids, flavanone, terpenes, flavone, flavonoids, aldehyde, volatile compounds, and monoterpenes in HLB-tolerant cultivars were much higher than susceptible. Various metabolic studies indicated that specific metabolites play a crucial role in limiting the spread and multiplication of the pathogens. Additionally, these metabolic signatures have the potential to be developed as markers for tolerance against HLB. Advanced tools like CRISPR/Cas9, metabolomics, and synthetic biology should be employed to validate the candidate genes involved in enhancing the production of compounds associated with HLB tolerance. The identified genes or SM could serve as valuable targets for citrus breeding, providing long-term solutions to combat HLB disease.