Teotihuacanin (1), an unusual rearranged clerodane diterpene with a new carbon skeleton containing a spiro-10/6 bicyclic system, was isolated from the leaves and flowers of Salvia amarissima. Its structure was determined through spectroscopic analyses. Its absolute configuration was established by single-crystal X-ray diffraction. Compound 1 showed potent modulatory activity of multidrug resistance in vinblastine-resistant MCF-7 cancer cell line (reversal fold, RFMCF-7/Vin+ > 10703) at 25 μg/mL.