Background The present in vitro study aimed to evaluate the fatigue behavior of teeth filled with a calcium silicate-based sealer (Bio-C Sealer, BC) or an epoxy resin-based sealer (AH Plus, AH), in bulk or associated with gutta-percha as main core material. Methods Seventy-two sound human maxillary anterior teeth were initially selected. Sixty of them, were randomly chosen, and had their root canals prepared using nickel-titanium reciprocating instruments, being again randomly assigned to five experimental groups (n = 12): C+ (control + prepared but not filled); BC-B (BC in bulk); BC-GP (BC+ gutta-percha); AP-B (AH in bulk); AP-GP (AH+ gutta-percha). An additional negative control group (C−) was considered (n = 12), consisting only on sound teeth, without preparation and filling. The specimens were submitted to a survival analysis after the cyclic fatigue test. Results Sound teeth (C−) presented the best fatigue performance (P < 0.05), being similar only to the AP-GP group (P > 0.05). Despite that, all experimental groups showed similar fatigue behavior (P > 0.05) to C+ (BC-B = BC-GP = AP-B = AP-GP = C+). Based on that, it can be seen that the use of gutta-percha, as a main core material, associated with the AH Plus sealer, reestablished the mechanical fatigue performance of endodontically treated teeth comparable to sound teeth, still consisting on the most promising approach to rehabilitate such scenario. Teeth filled in bulk, had discreetly higher risk of premature failures and inferior fatigue performance.