In the present work, we report the mechanism of a very large increase in the two-photon (TP) activity of squaraine based molecules upon changing the substituents. The replacement of a specific fused ring by ethylene or ethyne moieties enhances the TP transition strength of these molecules up to the order of 1013 au (∼1010 GM), both in the gas phase as well as in dichloromethane solvent. Our calculations decisively establish that the reason for this large enhancement in the TP activity of the studied systems is the severe decrease in the corresponding detuning energies. We explain this fact using damped response theory calculations and provide a novel design strategy to control the detuning energy of such molecules. The results are benchmarked against the available experimental findings. © 2014 the Partner Organisations.