PURPOSE: Three-level hybrid surgery (HS) consisting of cervical disc arthroplasty (CDA) and anterior cervical discectomy and fusion (ACDF) has been partly used for the treatment of multi-level cervical degenerative disc disease (CDDD). The complications related to the implants and the collapse of the surgical vertebral bodies had been reported in multi-level anterior cervical spine surgery. Thus, this study aimed to explore the biomechanical effects on the prostheses and vertebrae in three-level HS. METHODS: A FE model of cervical spine (C0-T1) was constructed. Five surgical models were developed. They were FAF model (ACDF-CDA-ACDF), AFA model (CDA-ACDF-CDA), FFF model (three-level ACDF), SF model (single-level ACDF), and SA model (single-level CDA). A 75-N follower load and 1.0-N·m moment was applied to produce flexion, extension, lateral bending, and axial rotation. RESULTS: Compared with the intact model, the range of motion (ROM) of total cervical spine in FAF model decreased by 34.54%, 54.48%, 31.76%, and 27.14%, respectively, in flexion, extension, lateral bending, and axial rotation, which were lower than those in FFF model and higher than those in AFA model. The ROMs of CDA segments in FAF and AFA models were similar to the intact model and SA model. Compared with the intact model, the ROMs at C3/4 segment in FFF model increased from 5.71% to 7.85%, and increased from 5.31% to 6.81% at C7/T1 segment, following by FAF model, then the FAF model. The maximum interface pressures of the Prestige-LP in FAF model were similar to SA model, however the corresponding values were increased in AFA model. The maximum interface pressures of the Zero-P were increased in FAF and AFA model compared with those in SF and FFF models. The stress was mainly distributed on the screws. In AFA model, the maximum pressures of the ball and trough articulation in superior and inferior Prestige-LP were all increased compared with those in SA and FAF model. In FFF model, the maximum pressures of the vertebrae were higher than those in other models. The stress was mainly distributed on the anterior area of the vertebral bodies. CONCLUSIONS: HS seemed to be more suitable than ACDF for the surgical treatment of three-level CDDD in consideration of the biomechanical effects, especially for the two-level CDA and one-level ACDF construct. But a more appropriate CDA prosthesis should be explored in the future.