The energy generation industry faces new challenges and requirements. The fourth generation of nuclear power plants is developed to meet the future clean energy demand by 2030. The supercritical carbon dioxide (S–CO2) Brayton closed cycle features compactness and high efficiency, combined with short construction time, standing for higher profitability when compared to current steam cycles. In this article, a method for assessing overall viability of direct and indirect carbon dioxide cycles is described. This method comprises both thermodynamic and economic analyses. Thermodynamic and economic models have been developed to assess several cycle designs in terms of overall viability that includes thermodynamic performance and financial outcome. Each cycle has been calculated through an iterative process that takes into account the variation of the properties of the working fluid and returns temperatures, pressure, efficiency, and power generation for the given design characteristics. The economic model, on the other hand, includes the calculation of overnight cost, which is a function of the cycle choice, through the cost of the components. Furthermore, plant profitability is calculated over a given period, which depends on both overnight cost and power plant efficiency. The method has been applied on an indicative parametric analysis of two S–CO2 cycles (direct and indirect) where the capability of identifying optimum areas has been case shown. In terms of overall pressure ratio, it was found that a thermodynamically optimized cycle would not coincide with an economically optimized one, due to the effect of component costing. On the other hand, turbine entry temperature appeared to considerably improve both power output and economic outcome, even though a maximum value is dictated by thermal and mechanical resistances of materials. In overall, even though power generation train is only a subsystem in a nuclear plant, it has been demonstrated that thermodynamic cycle design can have a significant impact on maximizing the earning capacity of the plant, especially through the implementation of a novel highly dense fluid, such as the S–CO2, which bears the potential of high compactness.