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Background: Non-small cell lung cancers (NSCLC) harboring Human Epidermal Growth Factor Receptor 2 (HER2) mutations represent a distinct subset with unique therapeutic challenges. Although immune checkpoint inhibitors (ICIs) have been transformative in lung cancer treatment, the efficacy of ICIs in HER2-mutated NSCLC remains to be established. Methods: We systematically searched for real-world studies investigating the use of ICIs in treating HER2-mutated NSCLC, sourced from the PubMed, Cochrane Library, and Embase databases. Outcomes including objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were extracted for further analysis. Results: Twelve studies involving 260 patients were enrolled in this meta-analysis. Pooled data revealed an ORR of 0.26 (95% CI 0.17–0.34), a DCR of 0.68 (95% CI 0.55–0.81), and a median PFS (mPFS) of 5.36 months (95% CI 3.50–7.21). Notably, in the subgroup receiving combined immune and chemotherapy, the ORR increased to 0.37 (95% CI 0.26–0.49), the DCR to 0.79 (95% CI 0.70–0.87), and the mPFS to 7.10 months (95% CI 5.21–8.99). Conclusions: ICIs demonstrate promising anti-tumor activity and safety in patients with HER2-mutated NSCLC. Furthermore, the combined regimen of ICIs and chemotherapy may provide a significant therapeutic option for this patient population. [ABSTRACT FROM AUTHOR]