Aim of the Study: The aim of this study was to compare the apical sealing ability of two single-cone filling materials when sealed with different types of root canal sealers. Materials and Methods: Eighty extracted maxillary and mandibular canines were selected and their crowns were cut. The root canals were prepared using ProTaper Universal rotary system until size F4 and then divided into seven experimental groups (n = 10 each) and two control groups (n = 5 each). Samples of Groups 1, 2, and 3 were filled with single-cone gutta-percha and AH Plus, MTA Fillapex, and EndoSequence BC, respectively. Samples of Groups 4, 5, and 6 were filled similar to the previous groups with the exception of using a single-cone CPoint. Samples of Group 7 were filled with cold gutta-percha lateral condensation technique. To assess apical microleakage, the apical linear dye penetration was measured microscopically and data were statistically analyzed. Results: All experimental groups showed significantly different dye apical leakage values (P = 0.000). No significant differences were found between Groups 1, 2, 4, 6, and 7 (P < 0.05). The lowest mean leakage value was observed in Group 6 (0.95 ± 0.56 mm) while Groups 3 (2.68 ± 0.71 mm) and 5 (2.61 ± 0.71 mm) showed significantly higher mean leakage values. Conclusions: The lowest apical leakage value was observed with single-cone CPoint/EndoSequence BC but without significant differences when compared with single-cone gutta-percha/AH Plus, single-cone gutta-percha/MTA Fillapex, single-cone CPoint/AH Plus, and lateral condensation technique. Higher apical leakage values were observed with single-cone gutta-percha/EndoSequence BC and CPoint/MTA Fillapex.