Introduction <p>Insulin resistance (IR) is a major determinant of cardiovascular disease and mortality, yet its direct measurement is limited by the need for insulin assays. The triglyceride–glucose (TyG) index has emerged as a simple and inexpensive surrogate marker of IR, but its prognostic relevance for mortality remains uncertain due to the heterogeneity of available studies.</p> Aim <p>This study aimed to: (i) evaluate the predictive value of the TyG index for all-cause and cardiovascular mortality risk in the general population; (ii) assess the shape and magnitude of the dose–response relationship; and (iii) identify the most appropriate threshold for mortality risk prediction.</p> Methods <p>A systematic review and dose–response meta-analysis was conducted, including prospective cohort studies that assessed baseline TyG and subsequent mortality. Random-effects models were used to pool hazard ratios, and restricted cubic splines were applied to examine potential non-linearity in the dose–response relationship.</p> Results <p>Twelve studies comprising 14 independent cohorts (≈10.8 million participants) were included. Each one-unit increase in TyG was associated with a 14% higher risk of all-cause mortality and a 16% higher risk of cardiovascular mortality starting from 6.9 units (or 3.79 units in the alternative scale). Associations were linear and consistent across sensitivity analyses. There was a significant heterogeneity among studies, but no evidence of publication bias.</p> Conclusion <p>The TyG index independently and linearly predicts all-cause and cardiovascular mortality, supporting its potential role as a clinically useful, low-cost marker for early cardio-metabolic risk stratification in population-based settings.</p> Graphical Abstract <p></p> <p>Insulin resistance is a key determinant of cardiovascular disease and premature death, but its direct measurement requires complex and costly tests. The triglyceride–glucose (TyG) index, derived from routine blood triglyceride and glucose levels, offers a simple surrogate marker. This systematic review and meta-analysis combined data from over 10 million participants in 14 population cohorts. Higher TyG values were consistently associated with greater risk of all-cause and cardiovascular mortality. Each one-unit increase in TyG corresponded to a 14% higher risk of death from any cause and a 16% higher risk of cardiovascular death, with risk rising steadily from about 6.9 units. Despite significant heterogeneity among studies, the associations remained robust and linear across analyses. These findings support the TyG index as a low-cost, independent, and clinically useful tool for early identification of individuals at higher cardio-metabolic risk in the general population.</p>