Fatigue crack nucleation in a powder metallurgy produced nickel alloy containing a non-metallic inclusion has been investigated through integrated small-scale bend testing, quantitative characterisation (HR-DIC and HR-EBSD) and computational crystal plasticity which replicated the polycrystal morphology, texture and loading. Multiple crack nucleations occurred at the nickel matrix-inclusion interface and both nucleation and growth were found to be crystallographic with highest slip system activation driving crack direction. Local slip accumulation was found to be a necessary condition for crack nucleation, and that in addition, local stress and density of geometrically necessary dislocations are involved. Fatemi-Socie and dissipated energy were also assessed against the experimental data, showing generally good, but not complete agreement. However, the local stored energy density (of a Griffith-Stroh kind) identified all the crack nucleation sites as those giving the highest magnitudes of stored energy.