Chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) are major global health burdens that often coexist, potentially amplifying disease severity through shared inflammatory and immune dysregulation mechanisms. This study aimed to elucidate the molecular interplay between these diseases, providing insights that could inform targeted therapies. Through integrative analyses, including differential gene expression, pathway enrichment, protein-protein interaction (PPI) networks, and tissue-specific expression profiling, we identified 38 genes central to the shared pathophysiology of COPD and TB. Key genes such as RELA, RELB, and PLK3 were consistently upregulated, underscoring their roles in chronic inflammation and immune signaling, while downregulated genes like IKBIP and MS4A6A highlighted suppressed immune pathways, potentially linked to immune evasion strategies. Pathway enrichment revealed significant involvement of NF-κB signaling, cytokine-mediated pathways, and metabolic adaptations, emphasizing their relevance in maintaining inflammation and pathogen persistence. PPI analysis identified regulatory hubs such as STAT1 and guanylate-binding proteins (GBP5, GBP1), highlighting their potential as therapeutic targets. Tissue-specific expression pinpointed the lungs and whole blood as critical sites of transcriptional activity, while single-cell RNA sequencing localized dysregulated genes to alveolar macrophages and epithelial cells, revealing their cell-specific roles in disease progression. These findings provide a foundation for understanding the shared molecular mechanisms underpinning COPD and TB, emphasizing immune signaling and metabolic regulation as potential therapeutic avenues. Further experimental validation and multi-omics studies are essential to translate these insights into clinical applications, addressing the complex interplay of these coexisting diseases.