Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) is a TNF superfamily cytokine primarily acknowledged for its ability to selectively induce apoptosis in cancer cells. Beyond its antitumor effects, recent literature emphasizes the pleiotropic functions of TRAIL in physiological states and acute/chronic non-malignant diseases indicating its potential to be a breakthrough in diagnostics. This review explores the current understanding of the dynamic role of circulating soluble TRAIL (sTRAIL) and its potential as both a diagnostic and prognostic marker. Multiple in vitro, in vivo, and clinical studies in a wide range of neoplastic and non-neoplastic diseases including infectious diseases have been carried out to explore the potential role of sTRAIL in disease pathogenesis and as well as the possibilities of using it as a diagnostic and prognostic marker. The expression of sTRAIL seems to be context-dependent suggesting further research, particularly towards establishing disease-specific cutoff values. However, the lack of standardization in the serum sTRAIL estimation and the absence of reference intervals remain significant barriers to its clinical application. Addressing these challenges is essential for using circulating sTRAIL as an accurate diagnostic and prognostic marker in clinical practice.