Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive loss of branched-chain amino acid (BCAA) catabolism promotes tumor development and growth. In human hepatocellular carcinomas and animal models of liver cancer, suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumors, though this was not observed in regenerating liver tissues. The degree of enzyme suppression strongly correlated with tumor aggressiveness, and was an independent predictor of clinical outcome. Moreover, modulating BCAA accumulation regulated cancer cell proliferation in vitro, and tumor burden and overall survival in vivo. Dietary BCAA intake in humans also correlated with cancer mortality risk. In summary, loss of BCAA catabolism in tumors confers functional advantages, which could be exploited by therapeutic interventions in certain cancers. Display omitted •BCAA catabolism is lost during the development and progression of multiple cancers•BCAA catabolic enzyme expression predicts tumor aggressiveness and patient survival•Tumors display increased BCAA content and enhanced mTORC1 activation•Dietary BCAAs correlate with tumor burden in mice and cancer mortality in humans Using a multi-omic approach to characterize normal, regenerating, and cancerous liver tissues in mice and humans, Ericksen et al. find that BCAA catabolism is lost during tumor development and progression, but maintained in normal proliferating cells. Tissue BCAA content is also influenced by dietary BCAA intake and affects mTORC1 activity.