This work investigates the heterogeneous deformation and failure of HR3C austenitic stainless steel welded joints at room and typical service temperatures. Such types of welded joints are widely used in the new generation of fossil fuel power stations and are known to suffer from premature high temperature failure. Observation of in-service failures revealed that cracks may nucleate either in the heat affected zone or in the weld metal. The main objective of this work is to identify the local microstructural conditions and stress–strain fields responsible for both ductile failure and micro-crack nucleation within the weldment at low and high temperatures, respectively. To that purpose, a novel multi-scale micromechanics-based modelling framework is proposed. It relies on representative weld microstructure models digitally reconstructed from electron backscatter diffraction measurements, and dislocation density-based crystal plasticity models to describe the behaviour of individual grains in each weld region. A novel thermo-dynamically consistent relation for the configuration stored energy per unit volume is derived from the crystal plasticity framework.The single crystal models are calibrated and validated from a combination of uniaxial tensile tests on cross-weld specimens using high resolution digital image correlation techniques, representative volume elements of the polycrystals at the macro-scale, as well as micropillar compression tests at the scale of the individual grains. Predictions of heterogeneous inelastic deformation fields within the weldment at both 22 °C and 665 °C, and of micropillar compression behaviour of the individual weld single crystal phases are consistent with experimental data. The experimentally observed ductile failure of the weld metal at room temperature is successfully predicted using a Gurson-type void nucleation, growth and coalescence constitutive model. The suitability of the stored strain energy density and the accumulated plastic strain as crack initiation/creep failure indicators is investigated. It was found that predicted creep lifetimes with either indicator were very similar, and that they were relatively accurate for low stress levels.