Objective <p>This study examined how system-matching gutta-percha (GP) cones in conjunction with calcium silicate-based sealers (CSBS) affect the sealing quality of canals prepared with variable taper nickel titanium (NiTi) files, using confocal laser scanning microscopy (CLSM) and micro-computed tomography (micro-CT).</p> Materials and methods <p>Forty-eight extracted human mandibular premolars were instrumented using the ProTaper Ultimate and divided into four groups based on GP cone (system-matching vs. non-matching) and sealer type (PlanB vs. TotalFill). Obturation was performed using the single-cone technique. Sealers were mixed with Fluo-3 dye for CLSM visualization. Micro-CT was used to quantify voids and gaps, while CLSM evaluated sealer penetration area and depth at the coronal, middle, and apical thirds.</p> Results <p>There were no significant differences in overall voids and gaps percentages between the cone systems (<i>p</i> = 0.66). System-matching cones however, significantly enhanced sealer penetration into dentinal tubules in terms of area, average, and maximum depth, especially in the apical third (<i>p</i> ≤ 0.001). PlanB demonstrated greater penetration area than TotalFill (<i>p</i> = 0.039).</p> Conclusion <p>The use of system-matching versus non-matching gutta-percha cones does not significantly affect the overall occurrence of voids and gaps in root canal fillings. However, system-matching cones improve sealer penetration into dentinal tubules, which differs among calcium silicate–based sealers. This emphasizes the importance of both cone fit and sealer selection in optimizing the quality of the single-cone obturation technique.</p> Clinical relevance <p>In canals prepared with variable taper NiTi files, both the compatibility of gutta-percha cones and the properties of calcium silicate–based sealers play a key role in enhancing the quality of the single-cone obturation technique.</p>