Abstract <p>A new series of acylated and alkylated derivatives of pyran-3-ylidene-1,5-benzodiazepine has been prepared, and their structures were confirmed using NMR spectroscopy. Additionally, five pyran-3-ylidene-1,5-benzodiazepine compounds were analyzed through single-crystal X-ray diffraction. Hirshfeld surface analysis was performed using several key parameters, including normalized contact distance (<i>d</i>_norm), external (<i>d</i>_e) and internal (<i>d</i>_i) distances, curvature, and fragment patches, which enabled detailed visualization of electron density and intermolecular interactions. Molecular docking studies were conducted to assess the binding affinities of these benzodiazepine derivatives to the gamma-aminobutyric acid (GABA) receptor [Protein Data Bank (PDB) identification code: 6HUP], using valium as a reference ligand. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling demonstrated that most compounds complied with Lipinski’s rules, exhibited good permeability through human colon carcinoma (Caco-2) cells, and showed low hepatotoxic and carcinogenic potential. The high passive permeability through Madin–Darby canine kidney (MDCK) cells and the absence of mutagenicity further support the potential of these compounds for development. Overall, the derivatives displayed improved profiles for advancement as clinical candidates based on in silico predictions, indicating that further experimental validation is required.</p>