Objective To evaluate the effect of ceramic thicknesses, bonding surface (enamel vs. dentin), and preparation design (box vs. no box) on the fatigue survival and failure load of minimally invasive full‐veneer restorations. Materials and Methods Human‐premolars (n = 60) were divided into five test groups (n = 12). All teeth received full‐veneer preparation with the following occlusal/labial thicknesses: standard: 1.5/0.8 mm; thin: 1.0/0.6 mm; ultrathin 0.5/0.4 mm. Preparations for each ceramic thickness were refined in enamel (E‐1.0 and E‐0.5) or dentin (D‐1.5, D‐1.0, and D‐0.5). Control groups DB‐1.5, EB‐1.0, and EB‐0.5 received box preparations. Monolithic lithium disilicate restorations (IPS‐e.max‐Press, Ivoclar Vivadent) were adhesively cemented (Syntac‐Classic/Variolink‐II, Ivoclar Vivadent) and subjected to cyclic mechanical loading (F = 49 N, 1.2 million cycles) with simultaneous thermocycling (5–55°C). All specimens were exposed to single load‐to‐failure. Pair‐wise differences were calculated by using a linear regression model and Student–Newman–Keuls method (p < 0.05). Results All full‐veneers of group D‐1.5, E‐1.0, E‐0.5, DB‐1.5, EB‐1.0, and EB‐0.5 survived fatigue. Two full‐veneers (D‐1.0 and D‐0.5) revealed cracks during fatigue, resulting in an overall fatigue survival rate of 98.1%. Mean load‐to‐failure values (N) were as followed: 1005 (D‐1.5); 866 (D‐1.0); 816 (D‐0.5); 1495 (E‐1.0); 1279 (E‐0.5); 1129 (DB‐1.5); 1087 (EB‐1.0); and 833 (EB‐0.5). Irrespective of ceramic thicknesses, enamel‐based full‐veneers resulted in higher failure loads than dentin‐based restorations. Box preparation reduced the failure loads of thin and ultrathin enamel‐based restorations. Conclusion All tested monolithic lithium disilicate full‐veneer restorations exceeded physiological masticatory forces. Minimally invasive full‐veneer restorations with enamel as a bonding surface and a non‐retentive preparation design showed superior performance. Clinical Significance Enamel‐based non‐retentive full‐veneers made of monolithic lithium disilicate may serve as a reliable and esthetical minimally invasive treatment option for premolars.