Aim <p>This systematic review aimed to synthesize current evidence on the regulatory role of microRNAs (miRNAs) in the viability, proliferation, osteo-odontogenic differentiation potential and/or inflammation of periodontal ligament stem cells (PDLSCs) and stem cells from the apical papilla (SCAPs), with a focus on their potential in periodontal and endodontic regeneration.</p> Methodology <p>A comprehensive search across Medline, Scopus, Embase, Web of Science, and SciELO databases up to December 2025 identified original in vitro studies assessing miRNA overexpression or knockdown in PDLSCs or SCAPs. 39 studies met the eligibility criteria and underwent structured data extraction, qualitative synthesis and quality appraisal using a tailored risk-of-bias tool (miRoB-DSC).</p> Results <p>The findings demonstrate that specific miRNAs act as key regulators of PDLSCs and SCAPs viability, proliferation, osteo-odontogenic differentiation, and inflammatory responses. Comparisons with previous reviews on DPSCs and PDLSCs suggest both shared and niche-specific regulatory networks. Various signaling pathways have been majorly implicated with miRNA regulation, including RUNX2, Smad/TGFβ, NOTCH, NF-κB, Wnt/β-catenin and MAPK. The majority of the assessed studies fulfilled more than 80% of the applicable items from the miRoB-DSC tool.</p> Conclusion <p>Collectively, these results highlight miRNAs as central modulators of PDLSC and SCAP biology, with potential applications as therapeutic targets or biomarkers in regenerative dentistry. However, heterogeneity in experimental designs, limited evaluation under disease-relevant conditions, and the reliance on in vitro models highlight the need for standardized protocols and in vivo validation before clinical translation.</p>