Breast cancer is common among women worldwide, and triple-negative breast cancer (TNBC) is characterized by an aggressive clinical course and high recurrence risk. Since hormone and targeted therapies are limited, radiotherapy is commonly used. However, existing treatments have clear limitations against radio-resistant TNBC, requiring new therapeutic strategies to overcome or bypass this resistance. In this study, we evaluated the effects of the natural compounds protocatechuic aldehyde (PA) and luteolin on radio-resistant MDA-MB-231 (MDA-MB-231/RR) cells following co-treatment by assessing cell viability and glucose metabolism and performing metabolomic and transcriptomic analyses using gas chromatography–mass spectrometry (GC-MS) and next-generation sequencing (NGS). Co-treatment with PA and luteolin synergistically reduced cell viability while inhibiting intracellular glucose metabolism. Furthermore, metabolomic and transcriptomic profiling revealed changes in glycine, serine, and threonine metabolism and alanine, aspartate, and glutamate metabolism pathways, along with a potential increase in oxidative stress. We also observed alterations in the MAPK signaling pathway, linked to inflammation-related pathways such as cytokine–cytokine receptor interaction and chemokine signaling, and cholesterol synthesis pathways. These results indicate that co-treatment with PA and luteolin could serve as a potential therapeutic strategy for radio-resistant TNBC.