Background Developing semicarbazide-based compounds as potential therapeutic agents is a promising direction in medicinal chemistry, particularly in the context of anticancer drug design. This study reports the synthesis and comprehensive physicochemical characterisation of a series of novel semicarbazide derivatives (AW8, AW12, AW19, AW23, AW33, AW38). Methods Molecular structures and tautomeric forms in the crystalline state were elucidated using single-crystal X-ray diffraction and supported by detailed Fourier Transform Infrared Spectroscopy (FT-IR) analysis. Incorporation into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-based model lipid membranes was evaluated using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and Langmuir monolayer techniques. Theoretical absorption, distribution, metabolism, and excretion (ADME) properties and in silico predictions were generated using SwissADME and ADMETlab 3.0 software platforms. Antioxidant potential was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays, and cytotoxicity against PANC-1 pancreatic cancer cells was determined using the 3-(4,5-di methyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results The compounds exhibited distinct hydrogen-bonding patterns, conformational preferences driven by substituent-dependent electronic effects, and characteristic supramolecular interactions governing their crystal packing, as confirmed by Hirshfeld surface analysis. Among the tested derivatives, AW8 and AW12 demonstrated the highest membrane affinity, inducing significant spectral alterations and surface pressure changes, indicative of enhanced membrane perturbation associated with chlorine substitution. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions revealed favourable pharmacokinetic profiles, including the potential for blood–brain barrier penetration in selected derivatives and predicted inhibition of P-glycoprotein, a key mediator of multidrug resistance. The compounds demonstrated moderate radical scavenging activity and dose-dependent cytotoxicity against PANC-1 cells. Conclusion These findings indicate that the studied semicarbazides exhibit promising membrane-active properties, favourable ADME profiles, and biological activity relevant to anticancer drug development, supporting their further evaluation as potential therapeutic candidates.