This paper presents a new hybrid chemical reaction optimization (HCRO) approach which is based on chemical reaction optimization (CRO) and differential evolution (DE) to find the optimal placement and parameter setting of unified power flow controller (UPFC) to achieve optimal performance of power system network. In the proposed algorithm, four elementary reactions, i.e., on-wall ineffective collision, inter-molecular ineffective collision, decomposition, and synthesis, are developed. Moreover, mutation operation of DE is integrated with inter-molecular ineffective collision and crossover operation is introduced in the inter-molecular collision, synthesis, and decomposition process to accelerate the convergence speed and improve the solution quality of CRO algorithm. Here, three different single objectives namely, minimization of the overall cost, transmission loss, voltage deviation and one multi-objective which simultaneously minimizes the transmission loss and voltage deviation are used. To verify the effectiveness, the proposed HCRO approach is implemented on IEEE 14-bus and IEEE 30-bus power systems. Moreover, to establish the superiority, the simulation results of the proposed HCRO technique are compared to the CRO and other previously reported algorithms published in the literature such as genetic algorithm (GA), particle swarm optimization (PSO), immune GA (IGA), immune PSO (IPSO) and hybrid immune algorithm (HIA). It is found that the results obtained by the proposed HCRO technique are superior to those obtained by other discussed algorithms.