Objective. The aim of this study was to identify the prevalence of orofacial alterations in sickle-cell disease (SCD) and to compare Study design. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. The search was conducted on PubMed, Embase, Scientific Electronic Library Online, Web of Science, Cochrane Library, gray literature, and references of the included articles. Results. A total of 770 records were found, and 28 studies were selected. In SCD, the prevalence of decreased bone density was 57% (95% CI: 35%-80%), with Q: P < .01 and I2 = 95%; for stepladder pattern was 30% (IC: 13%-47%), Q: P < .01 and I2: 93%; for delayed eruption was 20% (95% CI: 6%-34%), with Q: P < .01 and I2 = 86, Q: P < .01 and I2 = 99%; and for malocclusion, 66% (95% CI: 39%-92%), Q: P < .01 and I2 = 98%. A high risk of bias was observed in relation to the sample size of the studies. A limited number of articles compared the prevalence of orofacial alterations in patients with SCD and healthy individuals. Conclusions. Decreased bone density, malocclusion, orofacial pain, tooth necrosis, eruption delay, periodontal disease, and neuropathies may be present in patients with SCD with variable prevalence. (Oral Surg Oral Med Oral Pathol Oral Radiol 2023;135:642-660)