<p>Toll-like receptors (TLRs) are central sentinels of innate immunity that bridge early pathogen recognition to long-term adaptive responses. They act as receptors recognizing pathogen-associated molecular patterns (PAMPs-highly conserved molecular motifs) and damage-associated molecular patterns (DAMPs- allow the innate immune system to distinguish “non-self” from “self”), making them critical players in the context of protective host defence and autoimmune disorders, thus regulating inflammation. This review provides a comprehensive summary of TLR ligands as immunomodulators, with an emphasis on their mechanistic underpinnings and translational potential in infectious disease, vaccine design, and autoimmunity. The article begins with outlining the structural features and signalling pathways of TLRs, explaining both MyD88-dependent and TRIF-dependent cascades that culminate in cytokine, chemokine, and type I interferon production. These pathways orchestrate a wide range of effector responses, from macrophage activation to T and B cell differentiation, highlighting TLRs as master regulators of immune response. Importantly, the review underscores the dualistic nature of TLR signalling: while TLR agonists can serve as potent vaccine adjuvants, chronic or dysregulated TLR activation can drive autoimmune pathology. The article highlights preclinical and clinical evidence for TLR ligands as vaccine adjuvants or therapeutic agents for autoimmune conditions, aiming to suppress pathophysiology. Collectively, this review highlights TLR ligands as versatile immunomodulatory tools with diverse applications and immense clinical potential. The detailed mechanistic insights, along with critical shortcomings in light of safety guidelines, provide a balanced perspective on TLR-targeted therapies. This can serve as a roadmap for harnessing TLR pathways, enabling researchers and clinicians to design next-generation vaccines, manage infectious diseases, and develop autoimmune therapies.</p>