Background Lung cancer is one of the most common malignant tumors at present. This study aimed to compare the diagnostic accuracy, complication rates, and predictive values of computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) and endobronchial-guided transbronchial lung biopsy (TBLB) for patients with central pulmonary lesions (CPLs) with a diameter ≥ 3 cm.Methods We retrospectively included 110 patients with CPLs with a diameter ≥ 3 cm who underwent preoperative PTNB and TBLB examinations, and ultimately underwent surgery to remove CPLs and obtained pathological results. Detailed information was collected, including age, gender, tumor location, postoperative hospital stay, techniques involved, and pathologic diagnosis. Data were processed using SPSS software (version 26.0; IBM Corp). Data were compared by t-test or chi-square test. P-value < 0.05 was considered statistically significant.Results All patients underwent surgical treatment at the department of thoracic surgery and obtained a final pathological diagnosis. The rate of positive predictive value (PPV) was comparable between the two methods, and the negative predictive value (NPV) was significantly higher in the PTNB group compared with the TBLB group. In addition, PTNB was more sensitive and accurate than TBLB. However, the PTNB group had a higher probability of complications and TBLB was a relatively safer examination method.Conclusion PTNB demonstrated a higher accuracy and sensitivity than TBLB in the treatment of CPLs with a diameter ≥ 3 cm, but the complication rates of PTNB are relatively high. These methods exhibited different diagnostic accuracies and therefore should be selected based on different medical conditions.