Introduction: Confocal laser endomicroscopy (CLE) has the characteristics of high resolution, real-time imaging, and no radiation, which is helpful for the precise and effective implementation of transbronchial cryobiopsy (TBCB). The study aimed to compare the efficacy and safety of TBCB combined with CLE (CLE group) or fluoroscopy (fluoroscopy group) in the diagnosis of interstitial lung disease (ILD). Methods: From a prospective randomized controlled trial, 80 patients with undiagnosed ILD or ILD requiring biopsy between January 2022 and November 2022 were randomly assigned to CLE group and fluoroscopy group. The rate to reach an etiological diagnosis of ILD, maximum cross-sectional area of specimens, operation time, and complications were compared between the two groups. Results: The rate to reach an etiological diagnosis in the CLE group was significantly higher than that in the fluoroscopy group (95.0% vs. 80.0%, p < 0.05), but there was no difference in the maximum cross-sectional area of the specimens (42.1 ± 10.1 mm2 vs. 41.5 ± 10.3 mm2, p > 0.05). In terms of operation time, the CLE group was significantly shorter than the fluoroscopy group (37.6 ± 10.6 min vs. 54.8 ± 24.9 min, p < 0.05). The bleeding volume in the CLE group was significantly lower than that in the fluoroscopy group (4.9 ± 3.6 mL/case vs. 9.0 ± 9.2 mL/case, p < 0.05). Further analysis showed that the incidence of moderate bleeding was also lower in the CLE group (20.0% vs. 75.0%, p < 0.001). In addition, the incidence of pneumothorax in the CLE group was significantly lower than that in the fluoroscopy group (0 vs. 25.0%, p < 0.001). Conclusions: Compared with simple fluoroscopy, the combination of CLE significantly improves the rate of etiological diagnosis, shortens the operation time, and reduces complications such as bleeding and pneumothorax.