Currently, although some studies have explored the association between the cardiometabolic index (CMI) and mortality, for the adult population in the United States, detailed and systematic research on the link between CMI and both all-cause and cause-specific mortality remains insufficient. This study included a general population of 12,845 individuals with complete data from National Health and Nutrition Examination Survey 2005 to 2018. Mortality data were extracted from the National Death Index up to December 31, 2019. Restricted cubic spline analysis was used to explore the nonlinear association between CMI and mortality. Additionally, stratified analyses, interaction tests, and several sensitivity analyses were conducted to assess the robustness of the results. Over an average follow-up period of 7.7 years, there were 1388 deaths from all causes, including 322 cancer deaths and 413 cardiovascular disease (CVD) deaths. Weighted Kaplan-Meier survival analysis showed an increasing incidence of all-cause mortality, cancer mortality, and CVD mortality from the lowest to the highest quartiles of CMI, with Log-rank P < .001, Log-rank P = .014, and Log-rank P < .001, respectively. After full adjustment, weighted Cox regression demonstrated a nearly linear increase in CVD mortality with increasing CMI; compared to the referent quartile, the hazard ratios for Quartile 2 were 1.69 (95% confidence interval [CI]: 1.16-2.46; P = .01), Quartile 3 were 1.69 (95% CI: 1.12-2.55; P = .01), and Quartile 4 were 1.77 (95% CI: 1.16-2.70; P = .01) (P for trend = .04). However, the association between CMI and all-cause mortality as well as cancer mortality was not significant based on COX regression (all P > .05). Restricted cubic spline analysis revealed a significant linear relationship between CMI and CVD mortality (nonlinear P = .051). Interaction analysis confirmed consistent associations between CMI and CVD mortality across all subgroups (all P interaction > .05). Additionally, sensitivity analyses confirmed the robustness of the results mentioned above. CMI demonstrates an almost linear increase in CVD mortality among the general adult population in the United States, while showing no association with all-cause and cancer mortality. This indicates a more direct impact of CMI on heart health and the development of CVD.