Alzheimer’s disease, a progressive neurodegenerative disorder, is characterized by memory loss, cognitive decline, and behavioral changes, with no therapies available to halt its progression. Newer therapies targeting BACE1, a key enzyme in amyloid plaque formation, have shown promise in clinical trials. However, they have been limited by side effects and insufficient efficacy in slowing cognitive decline. Current treatments, including phase III BACE1 inhibitors such as atabecestat, elenbecestat, lanabecestat, and verubecestat, have shown limited efficacy. This is the first study where multi-ligand simultaneous docking (MLSD) was employed to identify potential synergistic inhibitor combinations from among thousands of small molecules that could yield better results than the current phase III inhibitors of BACE1. A library of 15,641 small molecules with known IC₅₀ values against BACE1 was filtered and docked, yielding binding affinities from −11.32 kcal/mol to +10.85 kcal/mol. Five small molecules with affinities ≤−11 kcal/mol and phase III inhibitors were tested as combinations for MLSD. Among 14 combinations tested, CHEMBL4078427 and CHEMBL3656158, CHEMBL4078427 and CHEMBL3695732, verubecestat and CHEMBL3656158, and CHEMBL4078427 and lanabecestat demonstrated superior binding affinities of −19.90 kcal/mol, −18.45 kcal/mol, −18.07 kcal/mol, and −17.67 kcal/mol, respectively, with inter-ligand interactions indicating synergy. Molecular dynamics simulations of CHEMBL4078427 with lanabecestat revealed enhanced BACE1 inhibition, showing lower root mean square deviation and radius of gyration compared to single-ligand inhibition. These findings underscore the transformative potential of MLSD in identifying synergistic compound interactions, paving the way for novel combination therapies in Alzheimer’s disease treatment.