Objectives To analyze the stress distribution and subsequent fracture resistance of human maxillary premolars with mesial-occlusal-distal (MOD) defects restored with different minimally invasive restorations. Materials and methods Seventy non-carious human maxillary premolars were selected and divided into seven groups (n = 10). Ten teeth without further preparation served as control. The remaining teeth were endodontically treated and received three restorative patterns: inlays without cusp coverage (I), onlays with palatal coverage (O), overlays with both buccal and palatal coverage (Ov). Lithium disilicate glass ceramics (EM) and machinable composite resin (LU) were used for restoration. Specimens were tested under cycling loading with tongue direction of 45° for 1.2 × 10 6 cycles at a 50-N load and 2.0-Hz frequency. The survival time and two fracture mode classifications were assessed. Three-dimensional models of each group were designed. The magnitude and pattern of stresses were analyzed under the same condition of the in vitro test using finite element stress analysis. Results Although the overlay model pattern produced more favorable stress distribution, three restorative patterns restored with the same material had no difference in survival curves ( P > 0.05). Only the survival curve of the EM-Ov group had no statistical difference with that of the control group ( P > 0.05). EM groups presented mainly interface adhesive failure, while LU groups were mainly material cohesive failure. Conclusion For the endodontically treated maxillary premolars with MOD defect, the lithium disilicate glass ceramic overlay pattern can reach the best restorative effect. Clinical relevance Comparing with restorative pattern, restorative material had a greater influence on the minimally invasive restoration of posterior teeth.