Background <p>This study aims to investigate the association between anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) and the risks of interstitial lung disease (ILD) and pneumonitis in patients with non-small cell lung cancer (NSCLC).</p> Methods <p>We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) reporting ILD or pneumonitis events, from inception to April 2024. Pairwise and network meta-analyses were performed. Outcomes were overall/serious ILD and pneumonitis.</p> Results <p>A total of 14 RCTs involving 3859 participants were included. Results showed that ALK-TKIs significantly increased the risks of both overall ILD (RD = 0.01, 95%CI: 0.00 to 0.02, <i>P =</i> 0.048) and overall pneumonitis (RD = 0.01, 95%CI: 0.00 to 0.02, <i>P =</i> 0.039) compared to chemotherapy, while no significant difference existed in the risks of both serious ILD (RD = 0.01, 95%CI: -0.00 to 0.02, <i>P =</i> 0.130) and serious pneumonitis (RD = 0.01, 95%CI: -0.00 to 0.02, <i>P =</i> 0.109) between ALK-TKIs and chemotherapy. In the network meta-analysis (NMA), brigatinib was associated with significantly higher risks of both overall ILD and overall pneumonitis compared to crizotinib (OR = 8.87, 95%CI: 1.07 to 73.29; OR = 3.43, 95%CI: 1.00 to 11.71, respectively), alectinib (OR = 12.78, 95%CI: 1.56 to 104.98; OR = 6.09, 95%CI:1.57 to 23.68, respectively) and ceritinib (OR = 32.50, 95%CI: 1.05 to 1005.95; OR = 21.88, 95%CI: 1.78 to 268.53, respectively). Furthermore, the NMA revealed that brigatinib was associated with a significantly higher risk of serious pneumonitis compared to ceritinib (OR = 27.26, 95%CI: 1.33 to 558.33).</p> Conclusions <p>ALK-TKIs increase the risks of both ILD and pneumonitis in NSCLC patients, with brigatinib posing the highest probability among ALK-TKIs.</p>