The detection of soluble proteins in biological fluids, as a form of liquid biopsy, is a promising tool for cancer diagnosis and prognosis, as it is less invasive than traditional diagnostic methods. CD44 is one of the most recognized markers of cancer stem cells, a small subset of cells responsible for cancer initiation, progression, and metastasis. Given the importance of CD44 as a cancer biomarker, several review articles explore the diagnostic and therapeutic value of cell-surface CD44. In addition to being a membrane-anchored protein, CD44 is also shed from the cell surface and can be found in various biological fluids. However, the role of soluble CD44 in cancer has not been comprehensively discussed in recent reviews. Measuring soluble CD44 in various biological liquids can provide a practical and valuable tool for cancer diagnosis and treatment monitoring. Therefore, this review comprehensively discusses the role of soluble CD44 as a marker in various cancer types, including serum, saliva, urine, and other fluids. In particular, its role as an early cancer biomarker and as a predictive and prognostic biomarker in several cancers is discussed. This work also provides an overview of a wide range of analytical techniques used to detect soluble CD44. The value of cells expressing CD44 versus soluble CD44 as a biomarker is also compared. The review concludes with a perspective on future directions, emphasizing the shift toward non-invasive analytical methods and the need for standardization of detection, including multiple biomarkers during evaluation, to improve the accuracy of cancer diagnosis.