The use of high-power lasers to reach the high temperatures typical for off-normal conditions in nuclear reactor fuel or to determine its properties at high temperature is a relevant and proven technique in the nuclear research community. Conducting studies at high temperature with full control in space and time of the thermal gradients is, however, a challenge. In this paper, we present a combination of methodologies, experiments, and models to drive nuclear fuel samples in thermal conditions relevant to the study of nuclear fuel materials. Based on the use of high-power (kW) lasers with beam shaping and temporal laser control, our experimental approach allows one to heat depleted UO2 samples and obtain precise control of the temporal gradients, in the ms range, and spatial gradients, in the 100 μm range. The coupling with numerical simulations allows one to determine the temperature distribution in the depth of the sample and to develop a thermo-mechanical interpretation of the results. We will present the methodology allowing one to properly compare experimental and simulation results by taking into account the optical response of the instrumentation, the laser–UO2 interaction, and the resulting heat source term. We will show that we can express the heat source term resulting from the laser loading either by an analytical description or statistically based on Monte-Carlo simulation. A fairly good agreement between the recorded temperature and the simulation results is shown. The presented methodology can be extended to other materials with a proper choice of laser wavelength and instrumentation based on the optical properties of the investigated material.