<p>This study aimed to evaluate the effect of different irrigation solutions and coronal barrier materials (CBMs) used in the regenerative endodontic treatment (RET) of simulated open-apex maxillary central incisors on the fracture resistance (FR) of the teeth by comparing them before and after chewing simulation (CS) application. The apical part of the roots of 132 permanent maxillary central teeth was cut, and a standard root length of 12&#xa0;mm was obtained. Teeth were randomly divided into 16 groups (<i>n</i> = 9 per group) and 4 control groups (<i>n</i> = 6 per group). The root canals of the teeth, except for the negative control group, were prepared. After root canal irrigation, CBMs were placed, and the teeth were restored with resin composite (3&#xa0;M ESPE, Germany). Mechanical and thermal loadings were applied using a multifunctional chewing simulator to replicate the forces and temperature changes encountered during functional use. FR testing was performed using a universal testing machine. Data normality was assessed with the Shapiro–Wilk test, and non-normally distributed values were analyzed using two-way robust ANOVA. A significant difference was found between groups regardless of CS application (<i>p</i> &lt; 0.001). The negative control group showed similar FR values to the EDTA + biodentine and etidronic acid + biodentine groups, but differed significantly from all other experimental groups (<i>p</i> &lt; 0.001). This study highlights the impact of irrigation solutions and CBMs on teeth’ FR values. Despite the study’s limitations, biodentine shows higher FR than TotalFill, while CS application does not affect the FR.</p>