<p>Tissue engineering creates possibilities for promoting bone regeneration, which can culminate in an ideal therapy for treating bone defects. Considering its tools, especially exosomes (Exos), inferring its efficiency is fundamental for future clinical protocols. Therefore, this research aimed to analyze, through a systematic review, the effectiveness of Exos therapy for regenerating bone. The study followed the PRISMA, and an electronic search for literature was performed until January 2024 to answer the PICO question: Would exosome therapy be effective for bone regeneration? Bone regeneration and cellular and molecular mechanisms were included in primary and secondary outcomes, respectively. The dosage, route of administration, and source cells have also been reported. The risk of bias was investigated according to the criteria of SYRCLE's RoB tool. The meta-analysis was executed using the standardized mean difference for bone mineral density (BMD) and volume ratio bone/whole bone (BV/TV) for cranial bone defects. A total of 3718 were examined, and after applying the eligibility criteria and excluding duplicates, 91 articles were included in the results. All studies demonstrated that Exos were effective in promoting regeneration of bone defects, being superior to the control groups established by each study included in this review, in most cases. The meta-analysis proved the superiority of Exos when BMD and BV/TV were analyzed. An increase in the levels of Runx2, ALP, OCN, OPN, CD31, COL-1, and VEGF, and presence of osteoblasts, M2-type macrophages, and endothelial cells, indicating osteogenic and angiogenic molecular and cellular mechanisms. The mesenchymal stem cells are the most commonly used origin cells. Exos dosage was varied, associated with scaffolds or hydrogels for application in bone defects. The risk of bias identified high scientific evidence for most domains. The Exos therapy is effective for bone regeneration and shows promise for this purpose.</p>