Although seafood is known to contain heart-healthy omega-3 fatty acids, many people choose to limit their seafood consumption because of fear of mercury exposure from seafood. It is imperative to clarify the potential health effects of current mercury exposure in contemporary populations. To examine the association of seafood consumption and mercury exposure with all-cause and cardiovascular disease (CVD)-related mortality in the US general population. This prospective cohort study included adults 20 years or older who participated in the 2003 to 2012 cycles of the National Health and Nutrition Examination Survey; data were linked to mortality records through December 31, 2015. Data analysis was performed from January to March 10, 2021. Seafood consumption was assessed through two 24-hour dietary recalls, and mercury exposure was assessed by blood mercury levels. All-cause and CVD-related mortality. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs of mortality associated with usual seafood consumption and blood mercury concentration quartiles. This study included 17 294 participants (mean [SD] age, 45.9 [17.1] years; 9217 [53.3%] female) with a mean (SD) blood mercury concentration of 1.62 (2.46) μg/L. During 131 276 person-years of follow-up, 1076 deaths occurred, including 181 deaths from CVD. The multivariable-adjusted HR for an increase in seafood consumption of 1 oz equivalent per day and all-cause mortality was 0.84 (95% CI, 0.66-1.07) and for CVD-related mortality was 0.89 (95% CI, 0.54-1.47). Blood mercury level was not associated with all-cause or CVD-related mortality. Comparing the highest with the lowest quartile of blood mercury concentration, the multivariable-adjusted HRs were 0.82 (95% CI, 0.66-1.05) for all-cause mortality and 0.90 (95% CI, 0.53-1.52) for CVD-related mortality. In this cohort study of US adults, seafood consumption and mercury exposure with the current seafood consumption level were not significantly associated with the risk of all-cause or CVD-related mortality. These findings may inform future public health guidelines regarding mercury exposure, seafood consumption, and cardiovascular health promotion.