Abstract: Non-competitive antagonists (NCAs) targeting the insect γ-aminobutyric acid receptor (GABAR) have great value in the field of insecticide research and development. As a representative compound, fluralaner has attracted considerable attention due to its potent insecticidal activity and target selectivity. In this study, the three-dimensional structure of the Musca domestica GABAR was constructed using the AlphaFold2 program. Molecular docking-based virtual screening was performed on 2.30 million compounds in the ChEMBL database, with fluralaner as the reference compound. Four hit compounds (ChEMBL5201664, ChEMBL3938339, ChEMBL467434, and ChEMBL1322496) were ultimately identified, exhibiting both higher docking scores and more favorable binding free energy than fluralaner. Subsequent 100 ns molecular dynamics simulations demonstrated favorable stability for the complexes formed by these hit compounds with GABAR. MM/PBSA binding free energy calculations revealed that the hit compounds exhibited substantially stronger binding free energies (−39.99 to −47.64 kcal/mol) toward GABAR compared to fluralaner (−33.16 kcal/mol) under dynamic solvation conditions, implying a potentially higher binding affinity. These findings suggest that the four hit compounds obtained through screening could serve as potential NCAs targeting insect GABAR, providing guidance for the design and development of novel insecticides.