Objective To study the mechanical properties of titanium mesh and three-dimensional (3D)-printed metal vertebral body substitutes (VBS) to provide guidance for the selection and structural optimization of artificial vertebral implants in clinical practice. Methods The equivalent elastic modulus, equivalent yield strength, and structural failure mode of titanium mesh and 3D-printed porous, truss, and topologically optimized VBS were systematically investigated using compression tests. Results The elastic modulus of the titanium mesh (2 908.73 ± 287.39 MPa) was only lower than that of the topologically optimized VBS. However, their structural strengths and stabilities were inadequate. The yield strength of the titanium mesh (46.61 ± 4.85 MPa) was only higher than that of the porous VBS and it was the first to yield during compression. The porous VBS was insufficient for use as the vertebral implant owing to its poor mechanical strength (18.14 ± 0.17 MPa–25.79 ± 0.40 MPa). The truss VBS had good elastic modulus (2 477.86 ± 55.19 MPa–2 620.08 ± 194.36 MPa) and strength (77.61 ± 0.50 MPa–88.42 ± 1.07 MPa). However, the structural stability of the truss VBS was insufficient, and instability occurred easily during compression. The topologically optimized VBS had the highest elastic modulus (3 746.28 ± 183.80 MPa) and yield strength (177.43 ± 3.82 MPa) among all the tested VBS types, which could provide improved security and stability for artificial vertebral implant in vivo services. Conclusions Topology optimization results in a high strength and high stability VBS design. Moreover, it provides a large design space and great safety margin to provide increased possibilities for lightweight and new material design of future artificial vertebral implants.