Until recent years, Sex Hormone-Binding Globulin (SHBG) has been considered of less a priority in the management of metabolic and chronic inflammatory states. However, emerging research highlights the remarkable role of SHBG in the screening and follow-up of patients not only with metabolic disorders but also in influencing reproductive outcomes. The present review aims to consolidate current knowledge on the involvement of SHBG in various clinical conditions. The search was performed using multiple databases to identify original studies measuring SHBG levels in conditions such as type-2 diabetes, metabolic syndrome (MetS), male obesity secondary hypogonadism, Polycystic Ovarian Syndrome (PCOS), male equivalent of PCOS, Nonalcoholic Fatty Liver Disease (NAFLD), infantile obesity, and early puberty. Among a total of 93,735 studies, 62 met the inclusion criteria, encompassing data from 127,771 subjects comprising both patients and controls. Studies were predominantly cross-sectional and observational cohorts, with MetS and NAFLD being the most extensively investigated conditions. Across all clinical conditions, significantly lower SHBG levels were consistently observed among patients compared to matched controls. The decrease in SHBG was found to be significantly associated with adverse reproductive, metabolic, and cardiovascular outcomes. These findings underscore the importance of considering SHBG as a valuable marker in routine clinical practice. Clinicians are encouraged to recognize the potential of SHBG as a useful marker in the assessment and management of various health conditions within their routine practice.