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Simple Summary: Lung cancer represents the most common form of cancer worldwide and the most frequent cause of cancer-related death in men and women combined. Lung cancer staging is very important, especially in patients who could benefit from surgery. Endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) are complementary techniques to explore and acquire tissue from mediastinal lymph nodes by trans-tracheal/bronchial and trans-esophageal approaches, respectively. The respective contribution of separate and combined procedures in the diagnosis and staging of lung cancer has not been fully studied. In our study, a total of 141 patients underwent both procedures, and the combined EBUS-EUS approach in lung cancer patients showed better accuracy and sensitivity in the diagnosis and staging of lung cancer when compared with EBUS and EUS alone. It demonstrated the unmissable aspect of the systematic combination of these endosonographic techniques for an optimal mediastinal diagnosis and staging in lung cancer for patients' survival. Background: Combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided tissue acquisition (EUS-TA) are accurate procedures for the diagnosis and staging of mediastinal lymph nodes (MLNs) in lung cancer. However, the respective contribution of separate and combined procedures in diagnosis and staging has not been fully studied. The aim of this study was to assess their respective performances. Methods: Patients with suspected malignant MLNs in lung cancer or recurrence identified by PET-CT who underwent combined EBUS-TBNA and EUS-TA were retrospectively reviewed. Results: A total of 141 patients underwent both procedures. Correct diagnosis was obtained in 82% with EBUS-TBNA, 91% with EUS-TA, and 94% with the combined procedure. The overall sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of EBUS-TBNA, EUS-TA, and the combined procedure for diagnosing malignancy were [75%, 100%, 100%, 58%], [87%, 100%, 100%, 75%], and [93%, 100%, 100%, 80%], respectively, with a significantly better sensitivity of the combined procedure (p < 0.0001). Staging (82/141 patients) was correctly assessed in 74% with EBUS-TBNA, 68% with EUS-TA, and 85% with the combined procedure. The overall sensitivity, specificity, PPV, and NPV of EBUS-TBNA, EUS-TA, and the combined procedure for lung cancer staging were [62%, 100%, 100%, 55%], [54%, 100%, 100%, 50%], and [79%, 100%, 100%, 68%], respectively, significantly better in terms of sensitivity for the combined procedure (p < 0.001). Conclusion: The combined EBUS-EUS approach in lung cancer patients showed better accuracy and sensitivity in diagnosis and staging when compared with EBUS-TBNA and EUS-TA alone. [ABSTRACT FROM AUTHOR]