Anterior lumbar interbody fusion (ALIF) uses a broad-footprint interbody cage designed to maximize fusion rates for treating degenerative disc disease. Bone graft substitutes are being increasingly utilized during ALIF to replace or supplement autologous iliac crest bone grafts. This approach aims to optimize fusion efficacy while minimizing associated postoperative complications. The objective of this systematic review was to examine recent studies on fusion rates and postoperative complications associated with bone graft substitutes used in ALIF. We conducted a systematic review of the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, MEDLINE, and PubMed databases, to critically examine a decade of research (January 1, 2012, to July 6, 2023) on the effectiveness and safety of various bone graft substitutes in ALIF. This timeframe was chosen to build on a previous systematic review published in 2013. The PRISMA guidelines were used. In total, 27 articles met our stringent inclusion and exclusion criteria. A substantial portion of these studies (67%) focused on recombinant human bone morphogenetic protein-2 (rhBMP-2) and highlighted its efficacy for achieving high fusion rates. However, the literature presents a dichotomy regarding the association of rhBMP-2 with increased postoperative complications. Notably, the methodologies for evaluating spinal fusion varied across studies. Only one-third of studies employed computed tomography to assess interbody fusion at 12 months postoperatively, highlighting the urgent need to establish uniform fusion criteria to facilitate more accurate comparative analyses. Moreover, there was considerable variability in the criteria used for diagnosing and detecting postoperative complications, significantly influencing the reported incidence rates. This review underscores the need for continued research into bone graft substitutes, particularly focusing on assessment of long-term complications. Future research endeavors should concentrate on developing comprehensive clinical guidelines to aid in the selection of the most suitable bone graft substitutes for use in ALIF, thereby enhancing patient outcomes and surgical efficacy.