An approach coupling experimental tests and numerical simulation of the pressure resistance welding (PRW) process is proposed for optimizing fuel cladding welds for the new generation of nuclear reactors. Several experimental welds were prepared by varying the dissipated energy, which accounts for the effect of electric current and welding time applied during the PRW process. A working zone, a function of both applied dissipated weld energy and plug-displacement, was then identified on the basis of the microscopy observations of the weld defects. In addition, the numerical approach, based on a 2D axisymmetric multi-physics finite element model, was developed to simulate the PRW process in a plug-tube configuration. The proposed model accounted for interactions between the electrical, thermal and mechanical phenomena and the electro-thermo-mechanical contact between the pieces and electrodes. Numerical simulations were first validated by comparison to experimental measurements, notably by comparing the plug-displacement and the size and position of the heat-affected zone (HAZ). They were then used to assess the effect of the applied parameters on the maximum temperature and cumulated plastic strain reached during welding and the effect of the welding force on the quality of the weld. According to the numerical computations, the maximum temperature reached in the weld remains well below the melting temperature. Changing the welding force implies also modifying the applied energy in order to maintain the quality of the welds. Applied to different plug and clad geometries, the proposed model was shown to be useful for optimizing the joint plane for such a welding configuration.