Recently, waste biomass-derived catalysts have emerged as sustainable and remarkable alternatives to petroleum (depleting resource)-based catalysts. We report here the application of a water extract of pomegranate peel ash (WEPA) as an effective catalyst in an aqueous medium for the construction of quinoxalines from aryl/heteroaryl 1,2-diamines and α-hydroxy ketones via a metal catalyst/added oxidant-free sequential condensation–cyclization–oxidation process with a sensible mechanism. The catalyst was systematically characterized using inductively coupled plasma mass spectrometry (ICP-MS), energy dispersive X-ray fluorescence (ED-XRF), Fourier transform infrared (FT-IR), powder X-ray diffraction (XRD), scanning electron microscopy(SEM), energy-dispersive X-ray spectroscopy (XEDS) and microwave plasma atomic emission spectroscopy (MP-AES) data. The quinoxalines were purified by recrystallization with excellent yields. The developed process shows very low E-factor (5.62 and 0.84 with and without the inclusion of water), along with multigram-scale (5.53 g) feasibility, and high regioselectivity in the case of unsymmetrical diamines and unsymmetrical α-hydroxy ketones. Furthermore, this method describes the use of a biorenewable catalyst and aqueous reaction medium for the construction of high-value heterocyclics and avoids volatile/problematic organic solvents, column-based product purifications, depleting material-based catalysts/axillaries/oxidants/purification agents/extraction agents and harsh reaction conditions. This biomimetic process can attract chemists’ attention towards identifying the applicability of waste biomass-derived catalysts for the production of fine chemicals and biopotent chemical substances involving novel/interesting processes.