Despite the widespread application of Ti6Al4V and tantalum (Ta) in orthopedics, bioinertia and high cost limit their further applicability, respectively, and tremendous efforts have been made on the Ti6Al4V-Ta alloy and Ta coating to address these drawbacks. However, the scaffolds obtained are unsatisfactory. In this study, novel high-interface-strength Ti6Al4V-based porous Ta scaffolds were successfully manufactured using Laser Powder Bed Fusion for the first time, in which porous Ta was directly manufactured on a solid Ti6Al4V substrate. Mechanical testing revealed that the novel scaffolds were biomechanically compatible, and the interfacial bonding strength was as high as 447.5 MPa. In vitro biocompatibility assay, using rat bone marrow mesenchymal stem cells (r-BMSCs), indicated that the novel scaffolds were biocompatible. Alkaline phosphatase and mineralized nodule determination demonstrated that the scaffolds favored the osteogenic differentiation of r-BMSCs. Moreover, scaffolds were implanted into rabbits with femur bone defects, and imaging and histological evaluation identified considerable new bone formation and bone ingrowth, suggesting that the scaffolds were well integrated with the host bone. Overall, these results demonstrated good mechanical compatibility, biocompatibility, and osteointegration performance of the novel Ti6Al4V-based porous Ta scaffold, which possesses great potential for orthopedic clinical applications.