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Simple Summary: Early cancer detection is a challenge in treating cancer patients. Remarkably, carcinomas of the breast, lung, liver, pancreas, ovary, and colon contribute to more than 50% of total incidences and mortality annually, which could be reduced by early detection. As mucins are highly upregulated during the early progression of these cancers, several studies have explored mucins as potential biomarkers. Due to their membrane-bound and secretory nature, mucins have been detected in tumor biopsies and liquid biopsies of cancer patients, including blood and urine samples. We compiled here previous studies advocating for the use of mucins as potential biomarkers for the early detection of cancer and discuss the opportunities and challenges related to the use of mucin biomarkers in combination with other biomarkers and detection modalities. Early detection significantly correlates with improved survival in cancer patients. So far, a limited number of biomarkers have been validated to diagnose cancers at an early stage. Considering the leading cancer types that contribute to more than 50% of deaths in the USA, we discuss the ongoing endeavors toward early detection of lung, breast, ovarian, colon, prostate, liver, and pancreatic cancers to highlight the significance of mucin glycoproteins in cancer diagnosis. As mucin deregulation is one of the earliest events in most epithelial malignancies following oncogenic transformation, these high-molecular-weight glycoproteins are considered potential candidates for biomarker development. The diagnostic potential of mucins is mainly attributed to their deregulated expression, altered glycosylation, splicing, and ability to induce autoantibodies. Secretory and shed mucins are commonly detected in patients' sera, body fluids, and tumor biopsies. For instance, CA125, also called MUC16, is one of the biomarkers implemented for the diagnosis of ovarian cancer and is currently being investigated for other malignancies. Similarly, MUC5AC, a secretory mucin, is a potential biomarker for pancreatic cancer. Moreover, anti-mucin autoantibodies and mucin-packaged exosomes have opened new avenues of biomarker development for early cancer diagnosis. In this review, we discuss the diagnostic potential of mucins in epithelial cancers and provide evidence and a rationale for developing a mucin-based biomarker panel for early cancer detection. [ABSTRACT FROM AUTHOR]