Non-small cell lung cancer (NSCLC) remains the most frequently diagnosed malignancy and the leading cause of cancer-related death worldwide. Although targeted therapies for actionable alterations and immune checkpoint inhibitors (ICIs) have improved outcomes, clinical benefit is highly heterogeneous, with frequent primary non-response and early acquired resistance. This unmet need has intensified the search for robust prognostic factors and predictive biomarkers. The human microbiota has emerged as a relevant candidate within this landscape, given its central role in immune modulation, systemic inflammation, epithelial barrier integrity, and the production of bioactive metabolites. Increasing evidence supports a gut-lung axis in NSCLC, with dysregulated intestinal and airway microbial profiles associated with aggressive phenotypes, metastatic patterns, and survival endpoints. Mechanistically, dysbiosis may influence tumor progression and therapy response through microbe-associated molecular pattern signaling and metabolite-driven effects on antigen presentation, interferon pathways, and regulatory T-cell balance, ultimately reshaping the tumor microenvironment. In immunotherapy, baseline gut microbiome features and iatrogenic perturbations have been linked to reduced ICI efficacy, while microbiota-restoring strategies such as fecal microbiota transplantation can rescue anti-PD-1 activity in translational models. Importantly, emerging data extend the relevance of the microbiome to oncogene-addicted NSCLC: baseline fecal signatures have been associated with the efficacy and gastrointestinal toxicity of Epidermal Growth Factor Receptor-tyrosine kinase inhibitors (EGFR-TKIs), and experimental microbiota perturbation can suppress EGFR-TKIs’ antitumor effects, whereas microbiota-supporting interventions may enhance response. Despite promising signals, inter-study variability and confounding exposures limit comparability. This narrative short review is based on a non-systematic search of PubMed/MEDLINE, Embase, and Scopus focused on NSCLC microbiome/gut-lung axis and outcomes with ICIs and EGFR-TKIs. Prospective, well-controlled multi-omics studies integrating microbiome, metabolome, immune profiling, and rigorous clinical annotation are needed to validate actionable signatures and define microbiota-informed strategies to optimize NSCLC treatment.