The aim of this study was to investigate the fracture behaviour of fissural dental enamel under simulated occlusal load in relation to various interacting factors including fissure morphology, cuspal angle and the underlying material properties of enamel. Extended finite element method (XFEM) was adopted here to analyse the fracture load and crack length in tooth models with different cusp angles (ranging from 50° to 70° in 2.5° intervals), fissural morphologies (namely U shape, V shape, IK shape, I shape and Inverted-Y shape) and enamel material properties (constant versus graded). The analysis results showed that fissures with larger curved morphology, such as U shape and IK shape, exhibit higher resistance to fracture under simulated occlusal load irrespective of cusp angle and enamel properties. Increased cusp angle (i.e. lower cusp steepness), also significantly enhanced the fracture resistance of fissural enamel, particularly for the IK and Inverted-Y shape fissures. Overall, the outcomes of this study explain how the interplay of compositional and structural features of enamel in the fissural area contribute to the resistance of the human tooth against masticatory forces. These findings may provide significant indicators for clinicians and technicians in designing/fabricating extra-coronal dental restorations and correcting the cuspal inclinations and contacts during clinical occlusal adjustment.