High-mobility group box 1 protein (HMGB1), one of the best described damage-associated molecular patterns (DAMP), is a chromatin concomitant nuclear protein. Inside the nucleus, HMGB1 acts as a formational chromatin-binding factor and facilitates the congregation of proteins such as p53, p73, Rel/NF-kB, estrogen receptor etc. on explicit DNA foci. Extracellularly, HMGB1 via the interaction with receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), to facilitate numerous biological functions like inflammation, cell migration, cell differentiation and cancer metastasis. Current studies have implicated HMGB1 as a key regulator protein in the pathogenesis as well as therapeutic potentials in cancer. The signaling mechanism via which HMGB1 advances clinicopathologically is also reconnoitered; however, advance studies are still desirable in some cancers. The mechanisms by which it contributes to carcinogenesis, and therapeutic strategies based on targeting HMGB1 mainly focus on biochemistry, molecular biology, and clinicopathology. Our review focuses on the clinicopathological and therapeutic role of HMGB1 in cancers.