Purpose There is a paucity of literature on symptom score (SS) plus fiberoptic bronchoscopy (FOB) –based response evaluation (RE) to chemotherapy for lung cancer. This study aimed to compare the reliability of RE by SS, chest radiograph (CXR), and FOB with computed tomography (CT) –based assessment (Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria) for lung cancer chemotherapy. Methods This was a prospective observational study involving treatment-naïve patients with lung cancer planned for chemotherapy, with one or more lesions on FOB and CT. Patients underwent assessment twice by SS, CXR, FOB, and CT (at baseline and after chemotherapy). Six symptoms (dyspnea, cough, chest pain, hemoptysis, anorexia, and weight loss) were noted on visual analog scale. Respiratory symptom burden (RSB) and total symptom burden (TSB) were calculated from the first four and all six symptoms, respectively, as the mean of individual SS. Bronchoscopic findings were recorded as per European Respiratory Society classification for tracheobronchial stenosis. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) by each method. For FOB and SS, improvement or worsening by ≥ 20% was taken as PR or PD, respectively, whereas < 20% change was considered SD. Agreements were tested using Cohen’s κ statistic. Results All individual SS, RSB, and TSB scores, and the number and distribution of FOB lesions improved significantly after chemotherapy. Individually, CXR and SS had no or minimal agreement with FOB-based and CT-based responses. RECIST and WHO criteria had strong agreement overall (Cohen’s κ = 0.872) and perfect agreement for PD (Cohen’s κ = 1.000). Cohen’s κvalues for FOB-based assessment with RECIST and WHO were 0.324 and 0.349, respectively for overall RE, and 0.462 and 0.501 for differentiating responders (CR and PR) from nonresponders (SD and PD), respectively. Cohen’s κvalues for PD were 0.629 (FOB alone), 0.672 (FOB and RSB), 0.739 (FOB and TSB), and 0.764 (FOB and CXR). Conclusion CT-based assessment should remain the reference for objective RE of chemotherapy in lung cancer. A combination of FOB and CXR may be used as a surrogate to diagnose PD if CT is not feasible.