Chalcones enable the biosynthesis of flavonoids which protect plants from infections and parasites and have emerged as valuable medicines against diverse human diseases. The common way to synthesize chalcones through the homogeneous catalytic Claisen-Schmidt condensation reaction is compromised from difficult catalyst recovery, waste generation, side reactions, and low yield. As a solution, solid base catalysts are developed as a green catalytic process. It is still a major challenge to synthesize highly active heterogeneous catalysts with a quick, simple, sustainable, and economical approach in the chalcone synthesis. To address these issues, a simple and sustainable synthesis of chalcones has been accomplished here by the solvent-free Claisen-Schmidt condensation reaction using magnesium oxide (MgO) nanosheets as the catalyst. The heterogeneous two-dimensional (2D) MgO catalyst was synthesized using salt recovered from inexhaustible seawater, using an atmospheric pressure plasma (APP)-assisted method making the whole method sustainable and potentially economically feasible. The catalytic activity of the 2D nanosheets was compared with irregular MgO nanoparticles. Irregular MgO showed 25% of benzaldehyde and 10% of acetophenone conversion, while 2D MgO showed >99% of conversion of both reactants with a product selectivity of 100%, while no products were formed in the absence of a catalyst. The effect of substituent groups on the benzaldehyde moiety on the catalytic activity was also analysed. The prepared 2D MgO catalyst showed reusability up to three cycles without any significant loss in the catalytic activity.