Cuspareine as an antiviral alkaloid can be used in the treatment of COVID-19. In this study, we introduced the ionic liquids (ILs) concluded cuspareinium as a cation with CH₃COO⁻, CF₃COO⁻, and PF₆ as anions. The optimized geometry, thermodynamic parameters, and reactivity descriptors were calculated with density functional theory (DFT) approach and time-dependent density functional theory (TD-DFT) using B3LYP/6-311G. In addition, the UV and IR spectra of the introduced ILs were investigated. Based on DFT calculation, the designed IL CH₃COO⁻ can be to the most suitable anions due to most solubility in the water. DFT studies displayed that all the introduced ILs have more polarity than pristine cuspareine and CH3COO⁻-cuspareine is the most polarity due to high dipole moment. Also, the thermo- chemical data of the designed ionic liquids revealed that PF6-cuspareine is distinguished to be stable. A molecular docking study of the designed ILs with 6 LU7 protease was performed to display interactions and binding energy. Results of molecular docking displayed that CH₃COO⁻ ion liquid has the highest binding energy (− 7.20 kcal/mol) and Ala7, and Lys 5 residues are involved in an interaction. DFT and molecular docking studies of cuspareine as alkaloid based on ionic liquids can be helpful to for more pharmaceutical and biological researches of cuspareine as an antiviral agent against COVID-19.