Various material properties are involved in the success of endodontically treated restorations. At present, restorative composites are commonly employed as core build-up materials. This study aimed to systematically review the literature to assess the effect of using composite core materials on the in vitro fracture of endodontically treated teeth. Two different reviewers screened the literature, up to June 2021, in five distinct electronic databases: PubMed (MedLine), Scopus, Scielo, ISI Web of Science, and EMBASE. Only in vitro studies reporting the effect of the use of composite core materials on the fracture resistance of endodontically treated teeth were included. A meta-analysis was carried out using a software program (Review Manager v5.4.1; The Cochrane Collaboration, Copenhagen, Denmark). The risk of bias in each study was assessed following the parameters of another systematic review. A total of 5016 relevant papers were retrieved from all databases. After assessing the title and abstract, five publications remained for qualitative analysis. From these, only three studies remained for meta-analysis. The fracture strength of endodontically treated teeth where a core build-up composite was used was statistically significantly higher than the control (p = 0.04). Most of the analyses showed a high heterogenicity. The in vitro evidence suggests that the composite core build-up with higher filler content tended to improve the fracture resistance of the endodontically treated teeth, in comparison with conventional composite resins. This research received no external funding. Considering that this systematic review was only carried out on in vitro papers, registration was not performed. Furthermore, there were no identified clinical studies assessing core build-up materials; therefore, more well-designed research on these materials is needed.