This study aimed to evaluate and compare the quality of matching single-cone obturation using three different single-file systems—WaveOne® Gold (Dentsply Sirona, Bensheim, Germany), Reciproc® blue (VDW GmbH, Munich, Germany), and Procodile® (Komet Medical, Gebr. Brasseler GmbH & Co. KG, Lemgo, Germany). The evaluation focused on the percentage of gutta-percha-filled areas (PGFAs), sealer-filled areas (PSFAs), and unfilled areas (PUAs) across three different sections of curved and straight root canals. Sixty extracted human teeth were categorized into six groups. Based on radiographically determined root canal curvature, thirty curved and thirty straight root canals were prepared using the single-file systems according to the manufacturers’ instructions and obturated with matching gutta-percha cones using AH-Plus sealer. A total of 180 sections were evaluated digitally under the microscope and the results were statistically analyzed. The mean gutta-percha percentages for Reciproc® blue, Procodile®, and WaveOne® Gold were 83%, 82%, and 80%, respectively. No significant (p > 0.05) and relevant (ηp2 < 0.10) differences were found in the proportion of form-fitting gutta-percha cones between the systems in all sections. Similarly, canal anatomy showed no significant influence (p > 0.05). Ex vivo, all three systems showed comparable filling quality in all sections of curved and straight canals. Therefore, it can be concluded that all three file systems, in combination with their corresponding gutta-percha points, might be reliable methods for root canal obturation. Reciproc® Blue, Procodile®, and WaveOne® Gold consistently achieved comparable obturation results across various root configurations and levels of the root canal.