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High-mobility group box 1 (HMGB1) is universally found in the nuclei and cytosols of mammalian cells. Excessive secretion of HMGB1 is concomitant with unrestricted replicative capabilities, angiogenesis, apoptosis, self-reliance in growth signals, neutrality to growth inhibitors, inflammation, tissue invasion and metastasis which are the cardinal indicators of cancer. HMGB1 levels are markedly elevated in cancers like colon, breast, lung, prostate, cervical, gastric, hepatocellular, leukemia, lymphoma and melanoma as compare to normal controls. Currently, clinicians rely on history, examination and radiological findings to diagnose as well as follow-up patients on treatment. This orthodox method has led to a “diagnostic gap” in several cancers. Therefore, this “diagnostic gap” could be filled with circulating biomarkers. Biomarkers can effortlessly be obtained via venipuncture, cost-effective and permit an appraisal of current transformations in cancer or therapy response via serial testing. This review focuses on the potential biomarker role of HMGB1 in predicting the prognosis as well as monitor therapy in various human cancers.