Synthetic ampicillin (AM)/starch (ST)/polymer composite nanofibers were fabricated during the electrospinning process, and it was found that the nanofibers had efficient and controlled drug release properties. AM, an antibacterial drug, was successfully encapsulated inside the ST-based composite nanofibers. The addition of biocompatible polymers, polyvinyl alcohol and polyethylene oxide, could efficiently improve the electrospinnability of ST aqueous solutions. The results of the density functional theory (DFT) calculation indicate that hydrogen bond interactions exist between AM and ST. Through the in vitro drug release studies, it was found that the AM release properties of the ST-based composite nanofibers could be controlled through manipulating drug loading, the ratio of ST to polymers, the species of polymers, and the weight of tablet. Graphical Abstract Synthetic ampicillin/starch/polymer composite nanofibers were fabricated during the electrospinning process, and it was found that the nanofibers had efficient and controlled drug release properties. The release of ampicillin from the starch-based composite nanofibers could be efficiently controlled through manipulating the ratio of starch to polymers, drug loading, species of polymers, and weight of tablets. Additionally, DFT calculation was used to investigate the interaction between ampicillin and starch. [GRAPHICS] .