<p>The present method involves a simple and highly efficient approach for the synthesis of a series of pyranopyrazole derivatives. The synthesis was achieved via a one-pot, four-component reaction of aromatic aldehydes, hydrazine hydrate, malononitrile, and β-keto ester in EtOH-H₂O by using a basic ionic liquid, i.e. 1-[3-(dimethylamino)propyl]-1,4-diazabicyclo[2.2.2]octan-1-ium hydroxide at ambient temperature. The synthesized compounds were characterized by FT-IR, ¹H, and ¹³C NMR spectroscopic methods. The attractive features of this protocol are higher yields (86–93%) within 20–22&#xa0;min, reusability of IL (up to 5 times), straightforward workup procedure, and purification of products by non-chromatographic methods, i.e. by simple recrystallization from ethanol. All the synthesized compounds have been screened for anti-inflammatory activity using the protein denaturation method. The in vitro anti-inflammatory evaluation has been supported by computational methods such as in silico assessment of ADMET and drug-likeness prediction, DFT calculation, and molecular docking study. In silico screening confirmed the potential of these compounds, all of which satisfied Lipinski's Rule of Five and exhibited strong binding affinities with Human COX-2 (PDB: 5KIR). Density Functional Theory (DFT) studies further elucidated the electronic structures of the synthesized pyranopyrazole, revealing favorable HOMO–LUMO energy gaps. This method provides a highly efficient route for synthesizing bioactive pyranopyrazole derivatives with promising pharmaceutical applications.</p> Graphical abstract <p></p>