Objective To investigate the method to prepare the ideal temozolomide-poly (lactic-co-glycolic acid) (PLGA) sustained-release nanoparticles used to control the growth of glioma cells and thus inhibit glioma.Methods The ultrasonic emulsification-solvent evaporation method was used to prepare the temozolomide-PLGA sustained-release nanoparticles. The surface morphological characteristics of sustained-release nanoparticles with four different molecular weights were tested, and their diameters were measured. Drug loading and encapsulation efficiency were measured, preparation parameters and morphological characteristics were analyzed, and release curves were plotted.Results The temozolomide-PLGA sustained-release nanoparticles had a stable structure and a uniform size, and their diameter increased with the increasing molecular weight. High-resolution light microscopy and electron microscopy showed that the nanoparticles had a smooth surface without any fissures, and the nanoparticles did not aggregate significantly and had a uniform size. The highest drug loading of temozolomide-PLGA sustained-release nanoparticles with different molecular weights was 10.2%, and their encapsulation efficiency was over 90%. The residual amount of methylene chloride was 5.70‰, which met the requirement for safe use in the brain. Release curves showed that temozolomide in the sustained-release system was released for more than 2 weeks, which met the requirement for interstitial chemotherapy cycle.Conclusions PLGA is a suitable carrier for the preparation of sustained-release nanoparticles, and the temozolomide-PLGA sustained-release nanoparticles meet the biomechanic rules. Although temozolomide has a burst effect, the drug release time can be controlled. Nanoparticles with different molecular weights and drug loadings can keep releasing temozolomide for a long time.