Objectives To assess related studies and discuss the clinical implications of endodontic access cavity (AC) designs. Materials and methods A systematic review of studies comparing the fracture resistance and/or endodontic outcomes between different AC designs was conducted in two electronic search databases (PubMed and Web of Science) following the PRISMA guidelines. Study selection, data extraction, and quality assessment were performed. Meta-analyses were undertaken for fracture resistance and root canal detection, with the level of significance set at 0.05 (P = 0.05). Results A total of 33 articles were included in this systematic review. The global evaluation of the risk of bias in the included studies was assessed as moderate, and the level of evidence was rated as low. Four types of AC designs were categorized: traditional (TradAC), conservative (ConsAC), ultraconservative (UltraAC), and truss (TrussAC). Their impact on fracture resistance, cleaning/disinfection, procedural errors, root canal detection, treatment time, apical debris extrusion, and root canal filling was discussed. Meta-analysis showed that compared to TradAC, (i) there is a significant higher fracture resistance of teeth with ConsAC, TrussAC, or ConsAC/TrussAC when all marginal ridges are preserved (P < 0.05), (ii) there is no significant effect of the type of AC on the fracture resistance of teeth when one or two marginal ridges are lost (P > 0.05), and (iii) there is a significantly higher risk of undetected canals with ConsAC if not assisted by dental operating microscope and ultrasonic troughing (P < 0.05). Conclusions Decreasing the AC extent does not necessarily present mechanical and biological advantages especially when one or more surfaces of the tooth structure are lost. To date, the evidence available does not support the application of TrussAC. UltraAC might be applied in limited occasions. Clinical relevance Maintaining the extent of AC design as small as practical without jeopardizing the root canal treatment quality remains a pragmatic recommendation. Different criteria can guide the practitioner for the optimal extent of AC outline form which varies from case to case.