The aim of this study was to explore the synthesis parameters of desogestrel-polylactic acid nanoparticles (DG-PLA-NPs), optimise the preparation technology, and elucidate the in vitro release characteristics. Considering encapsulation efficiency (EE) and drug loading as the main evaluation indexes, DG-PLA-NPs were prepared using the modified emulsion solvent diffusion method and single factor and orthogonal design tests were performed to investigate the influencing factors and optimise the preparation method. Morphology of the nanoparticles was observed using transmission electron microscopy (TEM), average particle diameter and distribution were determined using dynamic laser particle size analysis, and the EE and drug loading were measured using reversed-phase high-performance liquid chromatography. Among the eight factors, the drug-to-material ratio, water-to-organic phase ratio, and polyvinyl alcohol (PVA) concentration significantly affected the NP EE. In the optimised formulation, the PLA/DG ratio, PVA concentration, and oil-to-water phase ratio were 5, 0.5%, and 5, respectively. The DG-PLA-NPs prepared with the optimised formulation were round or spherical with an average diameter of 209 nm, 79.60% EE, and 6.81% drug loading capacity. The polydispersity index was 0.181, and the zeta potential was −27.37 mV. The in vitro releases of both DG and DG-PLA-NPs conformed to the Weibull equation. The DG-PLA-NPs released desogestrel rapidly in the early stages but slowly at later stages, indicating that compared to DG, the DG-PLA-NPs had obvious sustained-release effects. The DG-PLA-NPs prepared by the modified emulsion solvent diffusion method were small, simple to prepare, and had high drug loading with promising application prospects.