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Tuberculosis (TB) primarily manifests as pulmonary TB (PTB), but extrapulmonary TB (EPTB) remains a major clinical challenge. Distinct diagnostic and therapeutic difficulties arise from differences in immune responses, pathogen behaviour and host susceptibility. However, the factors driving disease localisation are still incompletely understood. We conducted a comprehensive narrative review of studies examining differences between PTB and EPTB in terms of epidemiology, mycobacterial factors, genetic and epigenetic determinants, host immune responses, transcriptomic profiles, cytokine and chemokine patterns, and immunophenotypes. EPTB is more common among females, children, older adults and immunocompromised individuals with deficient granuloma formation. This review is intended to provide deeper insight for clinicians and researchers and provides an accessible synthesis of current basic science findings together with their relevance for clinical practice. Certain Mycobacterium tuberculosis lineages, notably lineage 1, and specific virulence factors are associated with extrapulmonary dissemination. While genetic polymorphisms influence TB localisation, no studies specifically addressing epigenetic predisposition to EPTB were identified. PTB typically is characterised by T-helper 1-driven immunity, high bacillary loads and robust macrophage activation, whereas EPTB involves compartmentalised immune responses, reduced cytotoxicity and broader cytokine variability. Transcriptomic analyses reveal site-specific gene expression differences and emerging diagnostic blood-based biomarkers show promise but require further validation. Cytokine profiles and immunophenotyping suggest greater immune exhaustion and regulatory T-cell activity in EPTB. We outline practical implications for diagnosis and management and highlight constraints in resource-limited settings and emphasise access and implementation considerations. Integrating these clinical and mechanistic insights can guide more timely recognition and tailored care.