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Glyoxalase I (GLO I) detoxifies the reactive glycolytic byproduct methylglyoxal (MG) and is frequently overexpressed in cancer cells. High GLO I expression is closely associated with resistance to anticancer drugs, including doxorubicin (DOX). However, the functional relationship between GLO I activity and DOX-induced cell death remains unclear. In this study, we investigated whether inhibition of GLO I enhances cellular sensitivity to DOX. Using non-small cell lung cancer cell lines with low (NCI-H460 cells) or high (NCI-H522 cells) GLO I expression, we found that NCI-H522 cells, which we previously reported to be highly sensitive to the GLO I inhibitor TLSC702 and to accumulate MG following GLO I inhibition, were more resistant to DOX than NCI-H460 cells. Cotreatment with exogenous MG significantly potentiated DOX-induced cytotoxicity through multiple cell death pathways, supporting a role for MG-related processes in modulating DOX responses. While simultaneous treatment with TLSC702 and DOX showed limited enhancement, pretreatment with TLSC702 followed by DOX markedly increased cell death in GLO I-high cells, suggesting that prior disruption of MG detoxification may sensitize cells to subsequent DOX exposure. This effect was accompanied by enhanced poly(ADP-ribose) polymerase (PARP) cleavage and was partially suppressed by caspase and autophagy inhibitors, indicating enhanced apoptosis with contributions from additional cell death pathways. Collectively, these results demonstrate that GLO I inhibition primes cancer cells for enhanced DOX-induced apoptosis, providing mechanistic insights into GLO I-associated chemoresistance.