Oral squamous cell carcinoma (OSCC) is expected to rise ca. 40 % by 2040. Rosmarinic acid (RA) has been recognized for its anticancer properties, although its role in OSCC has been neglected. This work exploits the activity of RA in 2D and 3D models of OSCC cells to compel a roadmap for its anticancer properties. The results demonstrated that RA significantly reduced cell mass and metabolic activity in a dose, time, and cell-type-dependent manner, predominantly in highly-invasive OSCC, without compromising normal mucosa in therapeutic doses. RA decreased mitochondria membrane potential and increased redox state, which was corroborated by pioneering observations on the metabolome landscape of OSCC cells (glutathione reduction and acetate and fumarate release). RA triggered autophagy, upregulating BNIP3 and BCNL1 and downregulating BIRC5. The upregulation of CADM1 and downregulation of VIM, CADM2, SNAIL1, and SOX9 highlighted the modulation of epithelial-mesenchymal transition and the remodeling of the extracellular matrix by the downregulation of MMP-2 and MMP-9. RA interacts with P-glycoprotein with the highest docking score of -6.4 Kcal/mol. The cell surface charge decreased after RA treatment (-22.6±0.3mV vs. -26.3± 0.3mV, p<
0.0001), suggesting a reversion of cell polarity and the impairment of invasion. RA also shrank the growth and the metabolic activity of multicellular tumor spheroids. Its modest protein binding with human saliva sheds light on its administration by the oromucosal route. Overall, this work supports the need for further research on the anticancer potential of RA in OSCC, either in monotherapy, combined with conventional treatments, or conveyed in nanosystems.