Aims Metabolic dysfunction, inflammation, and lipoprotein(a) [Lp(a)] reflect different biomarker domains associated with atherosclerotic cardiovascular disease (ASCVD) risk. We examined the individual and joint associations of the triglyceride–glucose (TyG) index, high-sensitivity C-reactive protein (hs-CRP), and Lp(a) with incident ASCVD. Coronary heart disease (CHD) and stroke were analyzed as exploratory subtype outcomes of ASCVD. Methods We included 320,506 UK Biobank participants free of ASCVD at baseline. TyG, hs-CRP, and Lp(a) were analyzed in quintiles, and elevated biomarkers were defined as values in the fifth quintile. Incident outcomes were assessed using multivariable-adjusted weighted Cox models. Results Over a median follow-up of 13.88 years, 32,743 ASCVD events occurred. Compared with the lowest quintile, the highest quintile of TyG, hs-CRP, and Lp(a) was associated with higher ASCVD risk, with hazard ratios (HRs) of 1.32 (95% CI 1.27-1.38), 1.36 (1.30-1.43), and 1.23 (1.19-1.27), respectively. In exploratory analyses of ASCVD subtypes, the associations appeared generally more pronounced for CHD than for stroke. ASCVD risk increased progressively with the number of elevated biomarkers: HRs were 1.18 (1.15-1.21), 1.48 (1.42-1.53), and 1.85 (1.68-2.03) for one, two, and three elevated biomarkers, respectively. When the eight possible biomarker combinations were examined separately, concurrent elevation of TyG, hs-CRP, and Lp(a) identified the highest-risk profile for ASCVD (HR 1.90, 95% CI 1.71-2.11). Conclusions TyG, hs-CRP, and Lp(a) provide complementary information for ASCVD risk stratification. Multi-biomarker profiling may help identify individuals with higher cardiometabolic risk than single-biomarker assessment alone.