The polymorphism and thermostability of nirmatrelvir, the main antiviral component of the oral COVID-19 treatment drug, were studied. Four polymorphs of nirmatrelvir were prepared by recrystallization methods. Among them, Form 1 and nirmatrelvir methyl tert-butyl ether solvate (Form 2) had been reported in the literature, while nirmatrelvir isobutyl acetate solvate (NMTW-IBAC) and nirmatrelvir ethyl acetate solvate (NMTW-EA) are two new solvates. The crystal structures were characterized by single-crystal X-ray diffraction, powder X-ray diffraction, thermogravimetric analysis and differential scanning calorimetry. The thermostability of polymorphism and crystalline transformation were also investigated by combining Hirshfeld surface analysis and interaction energy analysis. The results showed that nirmatrelvir Form 1 belongs orthorhombic crystal system with the space group P2₁2₁2₁ and one nirmatrelvir molecule included in the asymmetric unit, which has the same crystal structure as nirmatrelvir Form 4 reported in the literature. Owing to its larger thermal expansion, the differences in crystallographic parameters obtained at different temperatures were found between Form 1 and Form 4. Three solvates of nirmatrelvir belonged to the iso-structural with monoclinic crystal system and the space group P2₁, in which the asymmetric unit contains one nirmatrelvir molecule and one solvent molecule. The thermal analysis results showed that nirmatrelvir Form 1 was a solvent-free crystal form with the best thermal stability and the strongest intermolecular hydrogen bonding. Among the three solvates, NMTW-EA has the worst thermal stability and the weakest hydrogen bonding interaction between the nirmatrelvir molecule and the solvent molecule. The energy framework of nirmatrelvir solvates showed that the closer the arrangement between solvent and nirmatrelvir molecules, the greater the total interaction energy between solvent and nirmatrelvir molecules. The phase transition studies of the three solvates showed that NMTW-IBAC and NMTW-EA were transformed into amorphous after desolvation, respectively, while Form 2 undergoes oiling during desolvation. The research provides theoretical guidance for the analysis, identification and quality control of nirmatrelvir polymorphs.