Due to the numerous environmental issues associated with fossil fuel power plants, using solar energy to generate electricity is a viable alternative. The organic Rankine cycle (ORC) is a thermodynamic process used to convert low- and medium-temperature heat sources into electricity, often utilizing organic fluids as the working medium. Entransy is a relatively new concept that many readers may not be familiar with. Moreover, entransy loss (Ġloss) is derived from the entransy concept, which quantifies the inefficiency in transferring thermal energy through a system. In this study, (Ġloss) is used for the first time when designing an ORC cycle coupled with parabolic trough collectors. The entransy loss relations were driven with assumption that the heat capacity is a function of temperature. A genetic algorithm is a search heuristic inspired by natural selection. It is used to find optimal or near-optimal solutions to complex problems by evolving a population of candidate solutions. Two scenarios utilized the genetic algorithm in MATLAB to optimize the system (scenario 1: maximizing the output power and scenario 2: maximizing the Ġloss). In addition, the optimization parameters included turbine inlet temperature (Ttur), boiler pressure (Pboil), condenser pressure (Pcond), and the temperature of the collector fluid at the boiler outlet (Thf,out). This optimization was performed for the temperature of the collector fluid at the boiler inlet (Thf,in) in the range 310–400 °C at 10 °C intervals with four working fluids (i.e., toluene, cyclohexane, MM, and water). The land area and the beam solar radiation were considered to be 100 hectares and 800 W/m2, respectively. The results indicated that according to scenario one, at temperatures of 310–320 °C, the maximum power was obtained for the case of toluene fluid with values 59.8 and 63.5 MW. For the collector fluid temperature from 330 to 400 °C, water had the most optimal power with values ranging from 66.2 to 88.2 MW. Furthermore, toluene exhibited superiority to two other organic fluids in the 330–400 °C temperature range after water, with net power values ranged between 65.7 and 76.3 MW. The results indicated that the maximum entransy loss does not correspond to the maximum output power because the application preconditions of the entransy loss concept are not all satisfied. Across all working fluids and Thf,in, scenario 2 resulted in lower optimal output power, cycle efficiency, and system efficiency compared to scenario 1.