Background/Objectives: Periprosthetic infection remains a major challenge in orthopedic implantation, particularly for porous titanium implants that promote bone integration but may also facilitate bacterial colonization. This study evaluated magnetron-sputtered tantalum–copper (TaCu) and niobium–copper (NbCu) coatings on Ti6Al4V implants following Staphylococcus aureus challenge, with particular attention to implant geometry. Methods: TaCu-coated, NbCu-coated, and uncoated Ti6Al4V implants with dense (smooth) or porous (rough) geometries were evaluated. Cytocompatibility was assessed using rat mesenchymal stromal cells exposed to implant-conditioned media, and Cu release was measured by ICP-MS. Twenty-four rabbits received femoral implants followed by local S. aureus inoculation. Outcomes were assessed by clinical observation, macroscopic examination, radiography, and confocal microscopy. DAPI-positive structures were analyzed three-dimensionally using a 100 μm³ volume threshold and sensitivity analysis. Results: Neither TaCu- nor NbCu-conditioned media adversely affected MSC metabolic activity, and both coatings released measurable Cu. Despite infection across groups, TaCu-coated implants showed the greatest preservation of implant retention. Analysis of 6,248 segmented objects from 21 animals showed significant associations of coating and implant geometry with the proportion of small DAPI-positive objects (both p < 0.001). Uncoated Ti6Al4V showed higher proportions than NbCu and TaCu (Holm-adjusted p < 0.001), whereas TaCu and NbCu did not differ (p = 0.731). Rough implants showed higher proportions than smooth implants, and the coating-related pattern persisted across thresholds of 25–200 μm³. An additional analysis using a 5 µm³ threshold confirmed differences in the relative proportions of very small DAPI-positive objects (p = 0.0156), whereas total volumetric object density did not differ significantly among coating groups (p = 0.769). Conclusions: Cu-containing coatings altered the distribution of implant-associated DAPI-positive structures without adversely affecting MSC metabolic activity. TaCu showed the greatest preservation of implant retention despite a confocal profile comparable to NbCu, supporting further investigation of TaCu for infection-resistant orthopedic implants.