Cotton is regarded as one of the significant economic crops in China, and its earliness is defined as one of the crucial traits influencing fiber quality and yield. To study the physiological and biochemical mechanisms related to early-maturing traits of cotton, cotton shoot apexes at the one-leaf, three-leaf, and five-leaf stages of the early-maturing cotton CCRI50 and late-maturing cotton Guoxinmian11 were collected for transcriptome sequencing and metabolomics, respectively. A total of 616, 782, and 842 differentially expressed genes (DEGs) at the one-leaf stage, three-leaf stage, and five-leaf stage were obtained through transcriptome sequencing, respectively. The metabolic detection results showed that 68, 56, and 62 differential metabolites (DMs) were obtained in the three periods, respectively. A total of 10 DMs were detected simultaneously from the one-leaf to five-leaf stage, 4 of which were phenolic acids and down-regulated in the early maturing variety CCRI50. A combined transcriptomic and metabolomic analysis revealed that phenylpropanoid biosynthesis, tyrosine metabolism, and phenylalanine metabolism might be important metabolic pathways in cotton bud differentiation.