The spice saffron () has anticancer activity in several human tissues, but the molecular mechanisms underlying its potential therapeutic effects are poorly understood. We investigated the impact of safranal, a small molecule secondary metabolite from saffron, on the HCC cell line HepG2 using untargeted metabolomics (HPLC-MS) and transcriptomics (RNAseq). Increases in glutathione disulfide and other biomarkers for oxidative damage contrasted with lower levels of the antioxidants biliverdin IX (139-fold decrease, = 5.3 × 10), the ubiquinol precursor 3-4-dihydroxy-5-all-trans-decaprenylbenzoate (3-fold decrease, = 1.9 × 10), and resolvin E1 (-3282-fold decrease, = 4), which indicates sensitization to reactive oxygen species. We observed a significant increase in intracellular hypoxanthine (538-fold increase, = 7.7 × 10) that may be primarily responsible for oxidative damage in HCC after safranal treatment. The accumulation of free fatty acids and other biomarkers, such as S-methyl-5'-thioadenosine, are consistent with safranal-induced mitochondrial de-uncoupling and explains the sharp increase in hypoxanthine we observed. Overall, the dual omics datasets describe routes to widespread protein destabilization and DNA damage from safranal-induced oxidative stress in HCC cells.