Fifteen annonaceous acetogenins (ACGs) with different stereochemical structures and configuration, representing three main classes of bis-adjacent-tetrahydrofuran (THF), bis-nonadjacent-THF, and mono-THF ACGs, were selected to tested for their inhibition activity on A549/Taxol cell line, which is multidrug resistant (MDR). The present study showed that some tested compounds showed significant activity toward A549/Taxol cells, and were more potent than the positive control Verapamil. For example, squamostatin-D (14) (IC50 value=16.19μM) was 7.8 times more active than Verapamil (IC50 value=127.09μM). Those ACGs with more carbons between the THF ring and the γ-unsaturated lactone were more potent. Moreover, ACGs with stereochemical arrangement of erythro were more active than those of threo, the compounds with THF ring configuration of cis seemed to be superior to those of trans. However, if all other structural features were identical, the ACGs with more hydroxyls on the aliphatic chain were not more potent towards A549/Taxol, which was not in accordance with previous studies. Furthermore, bis-nonadjacent-THF ACGs whose molecular weight is 622, with three hydroxyl groups located at carbon 16, 19, 24 and stereochemical arrangement of erythro possibly produced notable cytotoxicity. Based on the above conclusions, we proposed a compound model that may be a promising anti-MDR cancer candidate drug in the future clinical trial.