In this study, a bioguided fractionation of <i>Plectranthus mutabilis</i> extract was performed by chromatographic methods. It yielded one new <i>nor</i>-abietane diterpene, mutabilol (<b>1</b>), and three known abietanes, coleon-U-quinone (<b>2</b>), 8α,9α-epoxycoleon-U-quinone (<b>3</b>), and coleon U (<b>4</b>). The abietane diterpenoid <b>5</b> was also tentatively identified using HPLC-MS/MS. Moreover, the extract profile and quantification of each isolated compound were determined by HPLC-DAD. Compound <b>4</b> was the major compound in the extract. Compounds <b>2</b>-<b>4</b> were found to be selective toward cancer cell lines and were able to inhibit P-glycoprotein (P-gp) activity in NCI-H460/R cells at longer exposure of 72 h and consequently revert doxorubicin (DOX) resistance in subsequent combined treatment. None of the compounds influenced the P-gp expression in NCI-H460/R cells, while the extract significantly increased it.