<p>The drug discovery process involves the development of strategies to provide privileged small molecules and allowing access to new potential therapeutic entities. In this work, an efficient process to access chromeno-pyrazolo[1,2-b]phthalazines and indazolo[1,2-b]phthalazines via the three-component reaction between 2,3-dihydrophthalazine-1,4-dione, aromatic aldehydes and 4-hydroxycoumarine/dimedone is described. The notable features of this method include a much milder procedure, a shorter reaction time, a wide range of functional group tolerance, and absence of any tedious workup or purification. This procedure avoids hazardous reagents/solvents and is thus an eco-friendly alternative to the existing methods. Synthesized compounds also evaluated for in silico based pharmacophore investigation to check plausible therapeutic potential. Importantly, the synthesized molecules were found to bind at the active site catalytic cleft of c-Jun N-terminal kinase (JNK3), a well-established anti-neurodegenerative drug target and also plays crucial role in cancer, obesity and diabetic conditions. Higher free energy of binding (− 11.70– − 8.20&#xa0;kcal/mol)) of the synthesized molecules with JNK3 than previously known JNK3 inhibitor J6F (− 6.5&#xa0;kcal/mol) suggest sturdy ligand binding. Moreover, binding stability is corroborated by all atomistic molecular dynamics simulation performed in physiologically simulated conditions as well as deep learning-based binding affinity (pK_<i>d</i>) predictions. The therapeutic potentials of the synthesized molecules have been postulated through the detailed structure function analysis and its interaction with their cognate physiological target. DFT investigations also studied for all the synthesized chromeno-pyrazolo[1,2-b]phthalazines and indazolo[1,2-b]phthalazines.</p> Graphical abstract <p></p>