Background <p>This study aimed to investigate the feasibility and clinical benefits of indocyanine green (ICG) inhalation for detecting air leak sites during video-assisted thoracoscopic surgery (VATS).</p> Methods <p>Between February 2023 and May 2023, a total of 288 patients underwent VATS were enrolled in this study. Among the population, 72 patients received ICG inhalation test following the traditional submersion sealing test. And 216 patients only underwent the submersion sealing test were matched using 1:3 propensity score matching analysis. The results of ICG inhalation test and the clinical outcomes were compared.</p> Results <p>In the ICG group, 48 air leak sites were detected in 25 patients (25/72, 34.7%). The conventional submersion sealing test identified 30 air leak sites, while the ICG inhalation test detected 47 sites. Among these detected air leak sites, 34 sites were repaired by suturing or stapling. The postoperative air leak rate in the ICG group (20.8%) was significantly lower than the control group (37.0%, P = 0.011). ICG inhalation test was a favorable factor for reducing postoperative air leaks (OR: 0.40; 95%CI: 0.20–0.78; P = 0.008).</p> Conclusions <p>The ICG inhalation test facilitates the identification of air leak sites that may have been overlooked in the conventional submersion sealing test. This technique is useful to reduce postoperative air leaks for patients undergoing VATS.</p> Trial registration <p>Chinese Clinical Trial Registry: ChiCTR2300067603 on January 13rd 2023.</p>