HER2 genomic alterations characterize a specific subset of NSCLC with potential therapeutic relevance. While most studies focus on populations from high-income countries, data from Latin America remains scarce. We retrospectively analyzed 13 HER2-mutated NSCLC cases from a single institution in Northeastern Brazil, integrating clinical, histopathological, immunohistochemical, and molecular findings. Predominant histological patterns included acinar and lepidic subtypes, with HER2 mutations primarily involving exon 20 insertions (A775_G776insYVMA) and frequent co-alterations in TP53, KRAS, and STK11. HER2 protein expression assessed by IHC showed low scores (0-2+) in most cases, while HER2 gene amplification was confirmed in one case by D-DISH and NGS. Tumor mutation burden was universally low. Treatment responses varied, with one patient receiving trastuzumab deruxtecan. Our findings highlight the molecular diversity and diagnostic challenges of HER2-mutated NSCLC in underrepresented populations, emphasizing the need for comprehensive molecular profiling and expanded access to targeted therapies.