Triple-negative breast cancer is an aggressive subtype of breast cancer with low 5-year survival rates, high 3-year recurrence rates, and no known therapeutic targets. Recent studies indicated triple-negative breast cancers possess an altered metabolic state with higher rates of glycolysis, mitochondrial oxidative phosphorylation, and increased generation and utilization of tricarboxylic acid cycle intermediates. Here we utilized label-free quantitative proteomics to gain insight into the anti-cancer mechanisms of a methanolic extract from the Central American plant Lippia origanoides on MDA-MB-231 triple-negative breast cancer cells. The L. origanoides extract dysregulated mitochondrial oxidative phosphorylation by suppressing the expression of several subunits of Complex I of the electron transport chain, and inhibited cellular metabolism by downregulating key tricarboxylic acid cycle enzymes, and mitochondrial lipid and amino acid metabolic pathways. Our study also revealed treatment with the extract activated the stress response, and pathways related to cell cycle progression and DNA repair. Overall, our results reveal new compelling evidence that the extract from Lippia origanodes triggers rapid irreversible apoptosis in MDA-MB-231 cells by effectively ‘starving’ the cells of metabolites and ATP. We continue to study the specific bioactive components of the extract in the search for novel, highly effective mitochondrial inhibitors to selectively target triple-negative breast cancer.