This study presented an optimisation study of two-stage vapour-phase catalytic glycerol reforming (VPCGR) using response surface methodology (RSM) with a central composite experimental design (CCD) approach. Characterisation through Brunauer–Emmett–Teller analysis (BET), small-angle X-ray scattering (SAXS), scanning electron microscopy coupled with energy dispersive X-ray analysis (SEM-EDX), atomic force microscopy (AFM) and particle X-ray diffraction (PXRD) were carried out to understand the physiochemical activity of the honeycomb morphology CuO/CeO2 catalyst. Notably, in this study, we achieved the desired result of glycerol conversion (94%) and H2 production (81 vol.%) under the reaction condition of Cu species loading (10 wt.%), reaction temperature (823 K), WHSV (2 h−1) and glycerol concentration (15 wt.%). From the RSM analysis, an optimum predicted model for VPCGR was obtained and further integrated into Microsoft Excel and Aspen Plus to perform an energy analysis of the VPCGR plant at a scale of 100 kg h−1 of glycerol feed. As a whole, this study aimed to provide an overview of the technical operation and energy aspect for a sustainable frontier in glycerol reforming.