<p>Thermodynamic analysis and optimization of a polygeneration system that operates under a cascade use of low-grade geothermal energy are presented. The polygeneration system considers the integration of an organic Rankine cycle (ORC), thermally activated refrigeration (TAR), and a subsystem for dehydration. Since these components can have different internal configurations, working fluids, and coupling variants, it is necessary to jointly determine the interrelationship among components and also determine the most appropriate thermodynamic conditions to achieve an integrated system with high energy efficiency at a reasonable cost. Aiming to achieve the above, in this work a thermodynamic analysis was carried out first, taking into account the temperature range of medium and low enthalpy geothermal resources. ORC cycle and TAR cooling system morphological variants and working fluids were considered, as well as design characteristics that most influence the effective use of geothermal heat. Secondly, to estimate system economic performance, a cost estimation model was developed. For the energy and economic modeling of the systems, data and technical assumptions were used according to information provided by manufacturers, as well as other similar systems reported in the technical literature. Subsequently, a multi-objective optimization was implemented and solved using a genetic algorithm considering the exergetic efficiency, the net present value (NPV), and investment cost as the objective functions. The results show that the most favorable integrated systems reached values from 48.51 to 53.74% for exergy efficiency, with positive values of the NPV for all cases. On the other hand, the analysis carried out allows obtaining technical–economic information to determine the morphology and working fluids of components, as well as the most general viable polygeneration plant configuration.</p>