Advanced microscopy characterisation and numerical modelling have been carried out to investigate oxygen diffusion and crack growth in a nickel-based superalloy under fatigue-oxidation conditions. Penetration of oxygen into the material and the associated internal oxidation, which leads to material embrittlement and failure, have been found from Focused Ion Beam (FIB) examinations. Applied fatigue loading tends to enhance the extent of internal oxidation for temperatures at 750°C and above. Using a submodelling technique, finite element analyses of oxygen penetration at grain level have been carried out to quantify the fatigue-oxidation damage and calibrate the diffusion parameters based on the measurements of maximum depth of internal oxidation. The grain microstructure was considered explicitly in the finite element model, where the grain boundary was taken as the primary path for oxygen diffusion. A sequentially coupled mechanical-diffusion analysis was adopted to account for the effects of deformation on diffusion during fatigue loading, for which the material constitutive behaviour was described by a crystal plasticity model at grain level. Prediction of oxidation-assisted crack growth has also been carried out at elevated temperature from the finite 2 element analyses of oxygen diffusion near a fatigue crack tip. A failure curve for crack growth has been constructed based on the consideration of both oxygen concentration and accumulated inelastic strain near the crack tip. The predictions from the fatigue-oxidation failure curve compared well with the experimental results for triangular and dwell loading waveforms, with significant improvement achieved over those predicted from the viscoplastic model alone.