U-bend double pipe heat exchangers (UDPHEs) are one of the simple and low-costing heat exchangers (HEs) which have been used in various energy and thermal engineering applications. In present study, a comprehensive sensitivity analysis and multi-objective optimization of the thermo-hydraulic and performance characteristics is done for Fe3O4/water nanofluid flow inside UDPHEs with longitudinal strip inserts. The flow is turbulent and all of the important fluid conditions (including nanoparticles concentration, Reynolds number Re and Prandtl number Pr) and geometric parameters (including the aspect ratio of longitudinal strip inserts AR and the diameter ratio DR) are taken into account in investigations. The optimization is carried out using by genetic algorithm (GA) with considering entropy generation number (EGN) and performance evaluation criteria (PEC) as objective functions. The results of sensitivity analysis illustrate that, among all of the parameters, the parameters of DR and AR respectively has the highest and lowest impact on all of the objectives. Also, the outputs of the optimization procedure are 0.02298, 22478.25, 3.1205, 3.4593 and 0.5175 for optimum value of, Re, Pr, AR and DR, respectively (the optimum value of objective functions is EGN(opt) = 0.002593 and PECopt = 1.8489).