Current skull repair biomaterials used in clinical surgery face problems such as unmatched mechanical properties and poor biocompatibility. To overcome these problems, the multilayer micro-lattice biomaterials (MB) combining both suitable mechanical properties and biocompatibility are proposed based on skull structural characteristics. The quasi-static compressive mechanical properties of MB are studied experimentally, numerically and theoretically, which are verified by experimental results. The typical deformations, such as distinct shear zone and stress concentration of nodes, are observed. The strength and modulus of the above MB specimens are in the range of 86.72 ± 0.84 to 197.73 ± 0.74 MPa and 2.99 ± 0.13 to 7.56 ± 0.54 GPa, respectively. Simultaneously, the properties of MB with gradient design, including positive, negative and hybrid gradient are investigated by finite element (FE) simulation. The MB with hybrid gradient can better match the structural characteristics of skull. Since the designed MB has out-of-plane compression characteristics comparable to that of skull and suitable biological space for cell growth, it can be implanted into the human body to matched surrounding skull tissue well. The insight of MB combining with design constraints of biomaterials provides a novel method for designing/tuning skull repair biomaterials that might result in the optimized clinical skull surgery effect.