The role of dietary components and their microbiota-derived metabolites in the initiation of lung cancer remains to be elucidated. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation, is critical for cancer development. The present study aimed to determine the cytotoxic, DNA-damaging, and metabolic effects of nutritionally relevant natural compounds and dietary metabolites in early-stage lung cancer cells and lung epithelial cell alterations. The results showed that natural compounds, such as sulforaphane, apigenin, quercetin, and gallic acid, reduced cell viability and glycolysis of stage 1 lung cancer cells. Sulforaphane and the quercetin metabolite, 3,4-dihydroxyphenylacetic acid, completely prevented the increase in glycolysis induced by hemin and PhIP in stage 1 lung cancer cells. In conclusion, natural compounds and metabolites demonstrate protective properties against early lung cancer development in vitro, via decreasing glycolysis. Evaluation of these properties in in vivo models under dietary interventions is warranted.