<p>This systematic review and meta-analysis evaluated the outcomes of regenerative endodontic procedures (REPs) performed in immature necrotic permanent teeth in animal models, comparing autologous platelet derivatives (PDs) with the traditional blood clot (BC) scaffold. Following PRISMA guidelines and a protocol registered in PROSPERO, a comprehensive electronic search was conducted of PubMed, Web of Science, and Scopus up to April 2025. Preclinical studies were included if they assessed REPs in immature permanent necrotic teeth with open apices and compared at least one experimental group treated with autologous platelet derivatives (PDs) to a BC control group. Two reviewers independently screened studies, extracted data, and evaluated risk of bias using the SYRCLE tool. Random-effects meta-analyses were used to combine trial results and account for expected methodological and biological heterogeneity. Histological outcomes were descriptively assessed due to substantial data heterogeneity. The search identified 836 records, of which 10 studies met the inclusion criteria (45 animals, 393 teeth). The follow-up periods varied (1, 2, 3, 6 months), and the animals were sacrificed at the end of the 3- and 6-month periods. Pooled analyses showed no statistically significant differences between PDs and BC groups across all time points for clinical and radiographical outcomes. Histologically, both scaffolds primarily promoted the formation of mineralized tissue resembling cementum or bone, whereas true pulp or dentin regeneration remained limited. In conclusion, the currently available preclinical evidence does not provide clear evidence of superiority of either platelet derivatives or blood clot scaffolds in regenerative endodontic procedures. Further standardized animal studies with longer follow-up and detailed tissue characterization are required. <i>PROSPERO registration number</i>: CRD420250492243, date of registration: April 2025.</p>