Background <p>To assess the effect of indirect ultrasonic activation on the root canal obturation with a premixed calcium silicate cement (CSC).</p> Methods <p>Twenty-six single-rooted premolars were sectioned to the length of 11&#xa0;mm. All the roots were instrumented using ProTaper Next instruments and randomly assigned to either the control (<i>n</i> = 4) or experimental (<i>n</i> = 22) groups according to root canal obturation methods. Root specimens allocated to experimental groups were obturated with Endocem MTA, with (group EMU) or without (group EM) indirect ultrasonic activation (<i>n</i> = 11/group). Root specimens obturated with gutta-percha served as positive and negative (after nail varnish coating) controls. Intraoral radiograph images were used to assess the presence or absence of voids in the coronal, middle, and apical thirds of each specimen. The specimens were connected to a nanoscale fluid filtration device to measure quantitative leakage data. Data was statistically analyzed with a significance level of 0.05.</p> Results <p>There was no significant difference in the voids formation between the two groups (<i>p</i> &gt; 0.05), but specimens in group EMU presented significantly higher quantitative leakage than those in group EM (<i>p</i> &lt; 0.05).</p> Conclusions <p>Within the limitation of this study, indirect ultrasonic activation of premixed CSC did not affect the void formation but presented higher quantitative leakage. Future research incorporating micro-CT imaging would enable a more precise and comprehensive analysis, providing valuable insights into the root canal obturation with premixed CSCs.</p>