This paper details the development of a systematic methodology using thermo-economic modeling that can be used to identify the optimal exploitation schemes of geothermal resources. A multi-period approach is used, integrating the superstructure of exploitable resources with the superstructure of conversion technologies and multiple demand profiles. In the example case, exploitable resources include an enhanced geothermal system, a deep aquifer, and a shallow aquifer. Power generating systems considered are organic Rankine cycles and both single and double flash steam cycles, which can be used for combined heat and power production. Heat pumps are also considered, as well as back up systems in case geothermal resources alone cannot fully satisfy demand. Periods considered for the demand profiles of district heating and cooling are summer, winter, inter-seasonal, and extreme winter and summer conditions. These are based on the city of Nyon, Switzerland for the example case. In the next step, process integration techniques are then used to design the overall geothermal system. The economic and thermodynamic performance of the system is then calculated. Finally, an evolutionary algorithm is employed to determine the optimal exploitation schemes and system configuration across the multiple periods, with exergy efficiency and annual profit as objectives.