The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise, such that the search for novel anti-cancer therapeutics is paramount. However, in MDR cancers, such as the overexpression of membrane transport proteins like P-glycoprotein (P-gp) or the modulation of Protein Kinases C (PKC) isoforms, continues to be a major impediment to effective therapy. Known for their medicinal properties, species from Plectranthus have reported cytotoxicity against various cancer cell lines, due to diterpenes, such as 7α-acetoxy-6β-hydroxyroyleanone (Roy) and 6,7-dehydroroyleanone (DeRoy). Based on molecular docking simulations, 10 semi-synthetic derivates of Roy that displayed strong P-gp interactions in silico were prepared. The antitumoral activity was evaluated in resistant human cancer cell lines NCI-H460/R and DLD1-TxR, showing three derivatives having the most prominent selectivity towards cancer cells, compared to normal lung fibroblasts MRC5. Moreover, they showed a reduction in P-gp activity in Rho123 accumulation and indicated P-gp inhibition in the DOX accumulation assay using the same resistant cell lines. Overall, it was demonstrated that three abietane diterpenoid derivatives induced P-gp inhibition in MDR cancer cell lines. As for the PKC activity, further analogues were tested as PKC (α, βI, δ, ε and ζ) modulators; one benzoylated derivative showed the ability to selectively activate PKC-δ, while the natural compound DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms. Further investigations are ongoing to prepare analogues of other biological active diterpenoids to obtain potential hits as P-gp and PKC modulators.