Guanidine‐based task‐specific ionic liquid 1,1,3,3‐tetramethylguanidine acetate [TMG][Ac]was found to be a very effective solvent for the synthesis of pharmaceutically important spirooxindole derivatives through one‐pot multicomponent reaction of substituted isatin, thiazolidine‐4‐carboxylic acid and naphthoquinone followed by the spontaneous dehydrogenation in excellent yields without using any reagent and catalyst. The TMG‐based ionic liquid could be recovered and used at least four times without considerable reduction in its activity. The advantageous features of the developed synthetic protocol are high atom economy, operational simplicity, shorter reaction time, easily handling, and environmentally benign. The structure and relative stereochemistry of final products was established by single crystal X‐ray structure and spectroscopic techniques. The synthesized compounds were subjected for DNA cleavage activity.