The biodegradable poly (lactic acid) (PLA) has received increasing attention based on compostability, environmental concerns and applications in biomedical devices and packaging. However, slow crystallization and embrittlement have severely limited its broad applications. Many researchers reported how to improve this limitation by adding nucleating agent to control the crystal superstructure of PLA and to accelerate its crystallization rate. Several chemicals suitability as nucleating agents for PLA such as talc and dihydrazide, carboxylamide, oxalamide derivatives, has been evaluated, however the nucleation mechanism of these nucleating agents and the method of proper nucleating agent selection were unknown. In this paper, structural characterization of PLA oligomers containing three units and common nucleating agents was carried out with Gaussian 09. The local minimum energy geometry, energy barrier and structure in vacuo at B3LYP/6-31G(d,p) level using density functional theory (DFT) first were optimized, then with evaluation of peak shifts in FTIR spectrum for an unit cell of single crystal, the best nucleating agent will be choose. The vibrational change associated with inter- and intra-chain interaction indicates that oxalamide derivatives change both the crystallization mechanism and crystalline morphology of PLA via strong hydrogen bond between the self-assembly oxalamide nucleating agents and PLA matrix. At last the nucleation effect and nucleation mechanism of the oxalamide nucleating agent were also studied via differential scanning calorimetery and recognized that crystallization rate and crystallinity of PLA was significantly increased by the incorporation of 0.1 to 1.0 wt% of oxalamide derivatives.