Background: The Salvia plant and their metabolites are well reported for their valuable therapeutic effects and as potential remedies for treatment of many diseases. Salvia libanoticum is an endemic species to Lebanon where its metabolites have never been investigated. Objectives: The objectives were to evaluate the potential of abietane diterpenes from the roots of Salvia libanoticum as anticancer agents and explore some essential chemical features. Materials and Methods: Crude extract from the roots of Salvia libanoticum was separated using chromatographic techniques and spectroscopic analysis. The anticancer activities of the isolated compounds along with the crude extract were evaluated against MDA-MB-231 breast cancer cells and HCT116 human colon cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: Eight abietane diterpenes were isolated to be royleanone (1), 6,7-dehydroroyleanone (2) orthosiphonol (3), horminone (4), 7α-acetylhorminone (5), taxoquinone (6), 8,9-epoxy-7-oxoroyleanone (7), and 7-oxoroyleanone (8). All compounds including the extract revealed dose-dependent inhibitory effects that varied between the two cell lines, indicating cell-type specificity and suggesting different cell-compound interactions. Discussion: The most effective compound was found to be 7α-acetylhorminone, with IC50 of 18 and 44 μM on HCT116 and MDA-MB-132 cells, respectively. The results suggested that oxygenated C7 is essential for the cytotoxic activity. Moreover, the carbonyl group at position C7 leads to higher activity than the hydroxyl group. Conclusion: This study reported the potential of abietane diterpinoids as anticancer agents. It also suggested Salvia libanoticum and its diterpinoids as promising remedies in colon and/or breast cancer therapy. Further studies are needed to explore the exact interaction of these compounds with cancer cells at molecular level.