The development of multidrug resistance (MDR) is one of the major challenges in the successful treatment of cancer. MDR is often associated with the P-glycoprotein efflux pump. Natural products are a source of promising lead compounds to overcome MDR and, among them, diterpenoids from Plectranthus spp. are known as P-gp modulators. Bioguided fractionation of P. mutabilis acetone extract led to the isolation of one new nor-abietane diterpene, mutabilol (1), and three coleon compounds (coleon-U-quinone (2), 8α,9α-epoxycoleon-U-quinone (3), and coleon U (4)). Moreover, an additional acetoxy derivative of an abietane diterpenoid was tentatively identified using HPLC-MS/MS. The compounds were quantified using HPLC-DAD and coleon U was found to be the major compound in the extract. Using computational studies, a biosynthetic relationship between compounds 2 - 4 revealed that both compounds 2 and 3 were formed directly from compound 4. Compounds 2 - 4 were found to be selective towards the cancer cell lines and their anticancer effect was not compromised by the P-gp activity in resistant NCI-H460/R cells. Importantly 2, 3, and 4 were able to inhibit P-gp activity in NCI-H460/R cells at longer exposure (72 h) and revert doxorubicin (DOX) resistance in combined treatment. None of the compounds influenced the P-gp expression in NCI-H460/R cells, while the extract significantly increased it. Our study identified abietane diterpenoids from P. mutabilis that can evade MDR in cancer cells and inhibit the P-gp activity in prolonged treatment.