A comprehensive study of thermo-economic analysis and practical conceptual design of miniaturized lead-cooled fast reactor (LFR) composing supercritical CO2 power cycle is proposed in order to promote the real application in the market. The thermodynamic model and economic model are established based on the following five supercritical CO2 (S-CO2) Brayton cycles integrating with the miniaturized LFR, separately. Moreover, the optimization algorithm is adopted to optimize the key parameters of five power cycles with the objectives of maximizing the system thermoelectric conversion efficiency and electricity production costs (EPC) simultaneously. The optimal cycle and optimum parameters are obtained for the integrated system. Furthermore, the structural parameters of key components are confirmed based on the above results. The main subsidiary systems are designed. Finally, the practical design of LFR composing S-CO2 power cycle is carried out. The results shown that various parameters have different effects on the thermodynamic-economic performance of the system. The higher inlet temperature of turbine is beneficial to improve both thermodynamic and economic performance of the system. With the ƞt,sys-EPC analyzed simultaneously, the recompression cycle is the optimal to operate with more working conditions. Its ƞt,sys is from 36.68% to 44.46%, and EPC is from 0.050 $·kW−1·h−1 to 0.055 $·kW−1·h−1).