As an economically important tree species, mulberry (Morus spp.) has exhibited a remarkable tolerance for salinity, drought and heavy metals. However, the precise mechanism of metabolome-mediated drought adaptation is unclear. In this study, two new mulberry varieties-'drought-sensitive guisangyou62 (GSY62) and highly drought-tolerant guiyou2024 (GY2024)'-after three days (62F or 2024F) and six days (62B or 2024B) of drought-stress conditions were subjected to transcriptome and metabolome analyses. The enrichment analysis demonstrated that the differentially expressed genes (DEGs) were mainly enriched in carbohydrate metabolism, amino acid metabolism, energy metabolism and secondary metabolite biosynthesis under drought-stress conditions. Notably, compared with the CK group (without drought treatment), 60 and 70 DEGs in GY2024 and GSY62 were involved in sucrose and starch biosynthesis, respectively. The genes encoding sucrose phosphate synthase 2 and 4 were downregulated in GY2024, with a lower expression. The genes encoding key enzymes in starch biosynthesis were upregulated in GY2024 and the transcriptional abundance was significantly higher than in GSY62. These results indicated that drought stress reduced sucrose synthesis but accelerated starch synthesis in mulberry.