In this study, crude extracts of Ganoderma lucidum (NGCs) were compared to the crude extracts of G. lucidum that has antler-like fruiting bodies (AGCs) for their cytotoxicity, inhibitory effects on the attachment of human immunodeficiency virus (HIV)-1 glycoprotein 120 (gp120) to cluster of differentiation 4 (CD4), identification and molecular docking simulations of chemical compounds to predict the best ligand inhibitor and the binding mechanism. Results showed that AGCs had a higher percentage of inhibition (54.3% ± 6.2%) at 150 ppm and higher cytotoxicity (half maximal cytotoxic concentration [CC50] < 300 ppm) than NGCs (CC50 < 400 ppm). Quadrupole time-of-flight (QTOF) liquid chromatography- mass spectrometry (LC-MS) results successfully identified 32 chemical compounds in AGCs and NGCs, comprising mostly ganoderic acids (62%) and their derivatives. Molecular docking simulations of ganolucidic acid A/D and ganoderic acid A/B predicted the strongest binding affinity via hydrogen bonding, suggesting the inhibition of HIV-1 gp120 attachment to CD4. The highest and lowest occupied molecular orbital (HOMO and LUMO, respectively) gap energies of ganoderic acids tended to have less negative HOMO energy and smaller HOMO-LUMO gap energy, implying increased interactions of ligands to the gp120 protein receptor. AGCs showed higher inhibition against HIV-1 gp120 than NGCs due to a higher abundance of ganoderic and ganolucidic acids, whereby both acids contributed the highest number of hydrogen bonds and polar interactions from the hydroxyl and carboxylic functional groups.