The purpose of this review was to compare the efficacy and safety of synthetic bone graft substitutes versus autograft or allograft for the treatment of lumbar and cervical spinal degenerative diseases. Multiple major medical reference databases were searched for studies that evaluated spinal fusion using synthetic bone graft substitutes (either alone or with an autograft or allograft) compared with autograft and allograft. Randomized controlled trials (RCT) and cohort studies with more than 10 patients were included. Radiographic fusion, patient-reported outcomes, and functional outcomes were the primary outcomes of interest. The search yielded 214 citations with 27 studies that met the inclusion criteria. For the patients with lumbar spinal degenerative disease, data from 19 comparative studies were included: 3 RCTs, 12 prospective, and 4 retrospective studies. Hydroxyapatite (HA), HA+collagen, β-tricalcium phosphate (β-TCP), calcium sulfate, or polymethylmethacrylate (PMMA) were used. Overall, there were no differences between the treatment groups in terms of fusion, functional outcomes, or complications, except in 1 study that found higher rates of HA graft absorption. For the patients with cervical degenerative conditions, data from 8 comparative studies were included: 4 RCTs and 4 cohort studies (1 prospective and 3 retrospective studies). Synthetic grafts included HA, β-TCP/HA, PMMA, and biocompatible osteoconductive polymer (BOP). The PMMA and BOP grafts led to lower fusion rates, and PMMA, HA, and BOP had greater risks of graft fragmentation, settling, and instrumentation problems compared with iliac crest bone graft. The overall quality of evidence evaluating the potential use and superiority of the synthetic biological materials for lumbar and cervical fusion in this systematic review was low or insufficient, largely due to the high potential for bias and small sample sizes. Thus, definitive conclusions or recommendations regarding the use of these synthetic materials should be made cautiously and within the context of the limitations of the evidence.