No evidence-based prosthetic treatment concept for 3-unit fixed-dental-prostheses (FDPs) on ceramic implants is currently available. Therefore, the aim of this in vitro study was to investigate the failure load and fatigue behavior of monolithic and bi-layer zirconia FDPs supported by one-piece ceramic implants. Eighty 3-unit FDPs supported by 160 zirconia-implants (ceramic.implant; vitaclinical) were divided into 4 groups (n = 20 each): Group Z-HT: 3Y-TZP monolithic-zirconia (Vita-YZ-HT); Group Z-ST: 4Y-TZP monolithic-zirconia (Vita-YZ-ST); Group FL: 3Y-TZP zirconia (Vita-YZ-HT) with facial-veneer (Vita-VM9); Group RL (Rapid-layer): PICN “table-top” (Vita-Enamic), 3Y-TZP-framework (Vita-YZ-HT). Half of the test samples (n = 10/group) were fatigued in a mouth-motion chewing-simulator (F = 98 N, 1.2 million-cycles) with simultaneous thermocycling (5–55 °C). All specimens (fatigued and non-fatigued) were afterwards exposed to single-load-to-failure-testing (Z010, Zwick). Statistical analysis was performed using ANOVA, Tukey’s post-hoc tests and two-sample t-tests (p < 0.05, Bonferroni-corrected where appropriate). All specimens withstood fatigue application. While the effect of fatigue was not significant in any group (p = 0.714), the choice of material had a significant effect (p < 0.001). Material FL recorded the highest failure loads, followed by Z-ST, Z-HT and RL, both with and without fatigue application. Taken together, all tested FDP material combinations survived chewing forces that exceeded physiological levels. Bi-Layer FL and monolithic Z-ST showed the highest resilience and might serve as reliable prosthetic reconstruction concepts for 3-unit FDPs on ceramic implants.