Zirconia ceramic (ZC) implants are becoming more common, but comparisons between preclinical histology and long-term clinical trials are rare. This investigation comprised (1) 8-year clinical follow-up of one-piece ZC or titanium (Ti) implants supporting full overdentures and (2) histomorphometric analysis of the same implants in an animal model, comparing implants with various surface treatments. Methods: (1) Clinical trial: 24 completely edentulous participants (2 groups of N = 12) received 7 implants (one-piece ball-abutment ZC or Ti; maxilla N = 4, mandible N = 3) restored with implant overdentures. Outcomes after 8-years included survival, peri-implant bone levels, soft-tissue responses, and prosthodontic issues. (2) Preclinical trial: 10 New Zealand sheep received 4 implants bilaterally in the femoral condyle: Southern Implants ZC or Ti one-piece implants, identical to the clinical trial, and controls: Southern ITC® two-piece implants with the same surface or Nobel (NBC) anodised (TiUnite™) surface. %Bone-implant contact (%BIC) was measured after 12 weeks of unloaded healing. Results: 8 of 24 participants (33%) of an average age of 75 ± 8 years were recalled; 21% of original participants had died, and 46% could not be contacted. 80.4% of implants survived; excluding palatal sites, 87.5% of Ti and 79% of ZC implants survived. All failed implants were in the maxilla. Three ZC implants had fractured. Bone loss was similar for Ti vs. ZC; pocket depths (p = 0.04) and attachment levels (p = 0.02) were greater for Ti than ZC implants. (1.7 ± 1.6 mm vs. 1.6 ± 1.3 mm). All implants in sheep femurs survived. %BIC was not statistically different for one-piece blasted surface Ti (80 ± 19%) versus ZC (76 ± 20%) or ITC® (75 ± 16 mm); NBC had significantly higher %BIC than ITC (84 ± 17%, p = 0.4). Conclusion: Short-term preclinical results for ZC and Ti one-piece implants showed excellent bone-implant contact in unloaded femoral sites. This differed from the long-term clinical results in older-aged, edentulous participants. While ZC and Ti implants showed equivalent performance, the risks of peri-implantitis and implant loss in older, completely edentulous patients remain a significant factor.