Fracture resistance is an important parameter used to predict the performance of indirect dental restorations. The purpose of this in vitro study was to assess the fracture load of posterior milled nanoceramic crowns, in comparison with the lithium disilicate crowns, after fatigue loading, for two different restoration occlusal thicknesses. Forty test metal dies were fabricated by duplicating a master metal model consisting of an anatomic abutment preparation of the maxillary first premolar for a single crown. The dies were divided into two groups of 20 each for the fabrication of nanoceramic (Lava Ultimate) and lithium disilicate (IPS e.max CAD) single crowns. Each material group was further divided into two sub-groups of 10 dies each, based on crown occlusal thickness, of 0.5-mm and 0.75-mm (n = 10). Dental Type V stone dies poured from polyvinyl siloxane impressions of the test metal dies were laboratory scanned in order to design and mill 40 ceramic crowns. The crowns were cemented on to the test metal dies with a self-adhesive resin luting cement. All crowns were thermocycled (2500 cycles) and mechanically loaded (250,000 cycles) in a chewing simulator followed by static loading until failure, and the values noted. The data were statistically analyzed by 2-way ANOVA and Tukey HSD post-hoc multiple comparison tests (α = 0.05). The mean fracture loads ranged from 1022 to 1322 N for nanoceramic crowns and from 1145 to 1441 N for the lithium disilicate crowns. Two-way ANOVA revealed insignificant differences between the nanoceramic and lithium disilicate crowns (p > 0.05) in terms of fracture load. Significant differences were noted in the fracture resistance of crowns based on occlusal thickness (303 N; p = 0.013) regardless of the material used. Multiple comparisons by Tukey HSD post-hoc test showed insignificant differences between the four material-occlusal thickness groups (p > 0.05). The nanoceramic crowns were found to be comparable with lithium disilicate crowns in terms of fracture load. The mean fracture loads of all of the tested crowns were within the normal physiological masticatory load limits. Based on the fracture-resistance results, nanoceramic crowns seem to be suitable for clinical use for the tested occlusal thicknesses.