In this work, we describe the use of Water Extract of Rice Straw Ash (WERSA) as an efficient sustainable approach for the Knoevenagel reaction and a reaction medium, in combination with glycerol as a co-solvent, without the employment of any additional catalyst, base, ligand, or promoter. The effect of WERSA as an alternative catalytic source increased the reagent solubility provided by glycerol, resulting in several α,β-unsaturated carbonyl compounds with yields between 83 and 98%. The easy isolation of these compounds arising from their low solubility in this medium allowed the WERSA/glycerol mixture to be reused even after five reaction runs while yielding excellent results. The versatility of this system was tested for the multicomponent synthesis of heterocyclic moieties, which are attractive targets for synthesis that have been of great interest due to their biological properties. In this sense, 9-phenyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (6a) was synthesized with an 83% yield, demonstrating a great opportunity to expand this protocol for the synthesis of valuable compounds in a sustainable approach without the use of any additional catalyst.