Zygomatic implants (ZIs) were developed as a graftless alternative to rehabilitate severely reabsorbed maxillae. This study aims to employ three-dimensional finite element analysis (FEA) to simulate the impact of external hexagonal implant connection (EHC) and internal hexagonal implant connection (IHC) on the stress distribution and fatigue lifetime within the ZI systems using parameters defined in ISO 14801:2016. Two ZI assemblies (Nobel Biocare and Noris Medical) were scanned in a micro-CT scanner and reconstructed using Nrecon software. Three-dimensional models were generated by Simpleware ScanIP Medical software. All models were exported to FEA software (ABAQUS) and subsequently to a fatigue analysis software (Fe-safe). A compressive 150 N load was applied at a 40° angle on the cap surface. A 15 Hz frequency was applied in the in silico cyclic test. The implant components had material properties of commercially pure grade 4 titanium (CPTi) and Titanium-6Aluminum-4Vanadium alloy (Ti64). Von Mises stress data, contour plots, and fatigue limits were collected and analyzed. EHC models exhibited higher peak stresses in implant components for both materials compared to IHC models. However, simulated bone support results showed the opposite trend, with higher stresses on IHCthan EHC models. The fatigue analysis revealed that assemblies with both designs exceeded ISO 14801:2016 number of cycles limits using Ti64, while CPTi groups exhibited comparatively lower worst life-repeats. In conclusion, ZIs with IHC were found to have a more homogeneous and advantageous stress distribution within both materials tested. Ti64 demonstrates a prolonged service life for both design connections.