A comprehensive exergy, exergo-economic and sustainability assessment of seven conventional to hybrid air-conditioning systems comprising direct and indirect evaporative coolers with direct expansion system, and their several combinations integrated into an 8-story domestic building for 5 different cities corresponding to arid, semi-arid, humid sub-tropical, tropical wet and dry, and tropical wet climatic zones across India are investigated based on simulation output from EnergyPlus. The exergetic performances are reported for varying dead state temperatures ranging from 5°C to 40°C while saturated humidity ratio and pressure at system outlet are two other dead state properties. The results reveal that the specific exergy of moist air and exergetic efficiency decrease with increasing dead state temperature and become least at a dead state temperature near to American Society of Heating, Refrigerating and Air-conditioning Engineers (ASHRAE) comfort temperature of 23°C. In arid, semi-arid and humid subtropical climates, the three-stage evaporative cooling system exhibited the lowest exergy destruction of 100 J kg−1 and the highest exergy efficiency of 90% at a dead state temperature of 40°C. The two-stage direct evaporative-direct expansion cooling system exhibited superior exergy efficiency of around 90% in tropical wet and dry and tropical wet zones. Further, the Grassmann diagram based on the climate of Hyderabad indicated that the three-stage cooling system is energetically and exergetically optimum with exergy destruction of 28.86%.