Background: Galangin (Gal) is a natural active flavonoid compound separated from the roots and rhizomes of Alpinia ofcinarum Hance. Modern pharmacological studies have shown that Gal has a variety of biological activities such as antitumor, antifungal, antibacterial, antiinflammatory, antiischemic stroke, suppressing vitiligo and Alzheimer's disease, etc., Objectives: In this study, our primary goal was to prepare a galangin self-microemulsion drug delivery system (Gal-SMEDDS) and evaluate the effect of free Gal and Gal-SMEDDS on the pharmacokinetic parameters of SD rats, and the protective effect of oxidative damage on human embryonic lung fibroblasts (HFL1) cells in vitro. Materials and Methods: Gal-SMEDDS was prepared by ethyl oleate, Cremophor CO 40, and PEG-400, and then evaluated by morphology, particle size, zeta potential, polydispersity index, entrapment efficiency, and the pharmacokinetic parameters. The oxidative damage model of HFL1 cells was established by the stimulation of H2O2. And the antioxidant effect of Gal-SMEDDS on HFL1 cells was evaluated by ROS fluorescence assay kit and Annexin V-FITC/7-AAD double staining cell apoptosis detection kit. Results: The average particle size of Gal-SMEDDS was approximately 21.33 nm, the polydispersity index was 0.096, the zeta potential was − 4.09 mV, and the entrapment efficiency was 96.74%. Compared with free Gal, the release of Gal-SMEDDS was improved in vitro release experiment. Cell experiments showed the anti-oxidant effect of Gal-SMEDDS was better than free Gal. In vivo pharmacokinetic experiments showed that the pharmacokinetic parameters of Gal-SMEDDS were better than that of free Gal. Conclusion: The SMEDDS effectively increased the oral bioavailability of Gal and improved its pharmacokinetic parameters, which were conducive to the anti-oxidant effect of Gal.