Immune‐checkpoint inhibitors represent the new standard of care in patients with advanced NSCLC who progressed after first‐line treatment. This work aim to assess any difference in both efficacy and safety profiles among Nivolumab, Pembrolizumab and Atezolizumab in pre‐treated NSCLC patients. Randomized clinical trials comparing immune‐checkpoint inhibitor versus docetaxel in pre‐treated patients with advanced NSCLC were included and direct comparison meta‐analysis of selected trials have been performed. Subsequently the summary estimates of Nivolumab, Pembrolizumab and Atezolizumab emerging from the direct meta‐analysis were selected to provide the pooled estimates of hazard ratio (HR) and relative risk (RR) for the indirect comparisons among these agents. A total of 5 studies met the selection criteria and were included in the meta‐analysis. Indirect comparisons for efficacy outcomes showed the RR for ORR nivolumab versus atezolizumab 1.66 (95% CI 1.07−2.58), pembrolizumab versus atezolizumab 1.94 (95% CI 1.30−2.90). No significant differences in both PFS and OS have been observed. Indirect comparisons for safety showed the RR for G3‐5 AEs nivolumab versus pembrolizumab 0.41 (95% CI 0.29−0.60), nivolumab versus atezolizumab 0.50 (95% CI 0.35−0.72). No significant differences in both pneumonitis and discontinuation rate have been observed. The results of this work revealed that nivolumab and pembrolizumab are associated with a significant increase of ORR as compared to atezolizumab and nivolumab is associated with a significant lower incidence of G3‐5 AEs as compared to the other drugs. These evidences could support the oncologists to select the best drug for each patient. What's new? In advanced non‐small cell lung cancer (NSCLC), failure of first‐line therapy is followed by the use of immune checkpoint inhibitors (ICIs), which have superior survival benefits compared to standard chemotherapy. Three ICIs are available for pre‐treated NSCLC patients: atezolizumab, nivolumab, and pembrolizumab. The present meta‐analysis examined differences in efficacy and safety profiles between these agents. Indirect comparisons of data on clinical outcomes from five studies included in the meta‐analysis reveal significant differences in efficacy and toxicity between atezolizumab and nivolumab and between atezolizumab and pembrolizumab. The findings warrant further investigation given their potential impact on drug selection for NSCLC patients.