Lettuce is one of the major fresh-cut products in the market. However, browning is the main cause of quality loss in fresh-cut lettuce during storage. Here, the effects of different hormones on the browning control in fresh-cut lettuce were investigated. Results showed that 6-Benzylaminopurine (6-BA) was the optimal hormone to delay the fresh-cut lettuce browning. Metabolome profiling showed that 392 metabolites were detected in fresh-cut lettuce, including 250 primary metabolites and 92 secondary metabolites. Five phenolic-related metabolites, including chrysin O-malonylhexoside, calycosin-7-O-glucoside, chrysoeriol 7-O-rutinoside, glycitin, and scopoletin, increased with browning but reduced by 6-BA treatment. Transcriptome profiling revealed that phenolic-related metabolites pathways, especially the scopoletin, were enriched by differentially expressed genes, supporting that 6-BA reduced the fresh-cut lettuce browning through transcriptional regulation of phenolic-related metabolites biosynthesis, and scopoletin could serve as a marker compound for browning prediction. These results suggest that 6-BA is a promising anti-browning agent for fresh-cut lettuce.