Mechanical failure of zirconia-based full-arch implant-supported fixed dental prostheses (FAFDPs) remains a critical issue in prosthetic dentistry. The option of full-arch implant treatment and the biomechanical behaviour within a sophisticated screw-retained prosthetic structure have stimulated considerable interest in fundamental and clinical research. This study aimed to analyse the biomechanical responses of zirconia-based FAFDPs with different implant configurations (numbers and distributions), thereby predicting the possible failure sites and the optimum configuration from biomechanical aspect by using finite element method (FEM). Five 3D finite element (FE) models were constructed with patient-specific heterogeneous material properties of mandibular bone. The results were reported using volume-averaged von-Mises stresses (σVMVA) to eliminate numerical singularities. It was found that wider placement of multi-unit copings was preferred as it reduces the cantilever effect on denture. Within the limited areas of implant insertion, the adoption of angled multi-unit abutments allowed the insertion of oblique implants in the bone and wider distribution of the multi-unit copings in the prosthesis, leading to lower stress concentration on both mandibular bone and prosthetic components. Increasing the number of supporting implants in a FAFDPs reduced loading on each implant, although it may not necessarily reduce the stress concentration in the most posterior locations significantly. Overall, the 6-implant configuration was a preferable configuration as it provided the most balanced mechanical performance in this patient-specific case.