Durian (Durio zibethinus Murr.), a prized tropical fruit native to Southeast Asia, is known for its unique texture and sweet-bitter aroma. To understand the primary and secondary metabolites influencing durian’s texture and aroma, an integrative approach combining electronic nose and tongue analyses, transcriptomics, and metabolomics was first applied to three popular durian varieties: Musang King (MK), Monthong (MT), and Kan Yau (KY). The study identified 82 non-volatile and 95 volatile differentially expressed metabolites, with MK containing higher levels of terpenoids and sulfur compounds, while MT exhibited elevated esters and lipid-derived volatiles, contributing to its distinctive sweetness and aroma intensity. In contrast, KY was enriched in phenolic acids and amino acid derivatives, which may influence its bitterness and umami taste. Transcriptomic analysis revealed 12 927 differentially expressed genes, with key metabolic pathways including carbon metabolism, amino acid biosynthesis, and lipid metabolism playing significant roles in distinguishing these varieties. Furthermore, network pharmacology analysis pinpointed 45 key non-volatile metabolites with potential health benefits, including flavonoids, lipids, and alkaloids, which were linked to anti-inflammatory, cardiovascular-protective, and neuroprotective properties. Notably, MK and KY contained bioactive compounds with potential anticancer effects, while MT was associated with metabolites beneficial for metabolic regulation. This study enhances our understanding of the genetic and metabolic basis underlying durian’s texture, aroma, and functional properties, providing a foundation for future breeding and functional food development.