OBJECTIVES: This systematic review and network meta-analysis aimed to compare different PMMA (polymethyl methacrylate) complete denture base manufacturing techniques by evaluating their mechanical properties. The objective was to determine which method-compression molding, injection molding, milling, or 3D printing-offers the best performance. DATA: In vitro studies investigating mechanical properties of PMMA denture base resins. SOURCES: Four electronic databases such as PubMed, Embase, Web of Science, and the Cochrane Library were screened for English language articles. Two independent researchers selected studies, extracted data, assessed risk of bias, and evaluated evidence certainty. RESULTS: A total of 17152 articles were found by electronic databases. Finally, 63 studies were analyzed, using random-effects model for network meta-analysis. The outcomes investigated were flexural strength, flexural modulus, surface roughness, impact strength, and Vickers hardness. Milling consistently ranked first or second across outcomes, excelling in flexural strength, modulus, and surface roughness. In contrast, 3D-printed denture bases demonstrated the lowest mechanical performance, highlighting the limitations of this technique at present. CONCLUSION: Milling is generally recommended for PMMA denture bases due to its superior mechanical properties across most outcomes, supporting its use in clinical settings. However, while promising, 3D-printed PMMA denture bases require further improvement to meet clinical performance standards.