Traditional experimental methods have their own limitations to obtain a deep understanding about the molecular mechanism of drug-cyclodextrin (CD) complexes. Thus, present research investigated the molecular interactions between poorly water-soluble drug Ketoprofen (KTP) and six commonly used CDs by combined experimental and modeling methods. Experimental characterizations of prepared KTP-CD complexes observed the crystalline changes and hydrogen bonding formations of KTP. The molecular dynamic simulations at revealed that three beta-CD derivatives had higher binding affinity with KTP. Thus, this research present that the combination of experimental and modelling methods could clearly reveal the molecular mechanism of drug-CD complexes.