Amarissinin F (1) and its 16-epimer (2) are two neo-clerodane diterpenoids isolated from the leaves and flowers of Salvia amarissima that occur as an unresolved epimeric mixture by chromatographic methods. The molecular structures of these compounds were deduced by the extensive analyses of their HRESIMS and their 1D/2D NMR data. Both compounds co-exist in the solid state as confirmed by single-crystal X-ray diffraction. In solution, both isolates appeared as the major compounds, which was corroborated by derivatization with Mosher reagents. However, the 1H and 13C NMR spectra demonstrated evidence for epimerization at C-20 and the possible interconversion of the 16-hydroxy-15,16-furanone to a 15-hydroxy-16,15-furanone, which was supported by a variable temperature 1H NMR analysis. The absolute configuration of compounds 1 and 2 was established by single-crystal X-ray diffraction and NMR. The cytotoxic effects of the isolated epimeric mixture (1 and 2) against a set of human cancer cells and the MDR modulatory activity in resistant MCF-7 breast cancer cells were explored.