Objective Isoflavones, a group of soybean nutrients, have been found to provide a wide range of benefits to the human body. The prospective cohort study aims to examine the association of dietary intake of isoflavones with all-cause mortality and heart disease mortality in the US. Materials and methods In this study, We conducted to explore the potential correlation of isoflavones (total isoflavones, genistein, and daidzein) intake with the risk of all-cause mortality and heart disease mortality. The mortality status and the heart disease cause of death were determined by NHANES-linked National Death Index public access files through December 31, 2019. The association of dietary isoflavones intake with all-cause mortality and heart disease mortality was analyzed by multivariate Cox regression model to compute hazard ratio (HR) and 95% confidence interval (CI), with adjustment for some demographic characteristics, lifestyle factors, and comorbidities. In addition, we employed Kaplan-Meier curves, subgroups and restricted cubic spline models to assess the effect of dietary isoflavones in different circumstances. Result The final study population was 11,979 participants, with 1423 participants determined as deceased (7.95%). After adjusting for multiple variables, the study identified an inverse relationship between total isoflavones [Hazard Ratio (HR) 0.85, 95% CI: 0.74-0.99], genistein [HR 0.82, 95% CI: 0.69-0.98], daidzein [HR 0.81, 95% CI: 0.70-0.94] and the incidence of all-cause mortality. Similarly, only high levels of intake daidzein [HR 0.73, 95% CI: 0.53-0.99] were no significantly associated with heart disease mortality. Additionally, a non-linear relationship was observed between dietary isoflavones and all-cause mortality in female participants (p-value for nonlinear < 0.05 and p-value for overall < 0.05). Conclusion Our findings suggest dietary intake of total isoflavones, genistein, and daidzein in the right amounts was associated with lower all-cause mortality and exhibited an association of results for mortality from heart disease with daidzein to diminish the chances of heart disease mortality. The present study reveals a U-shaped association between dietary isoflavones and all-cause mortality in female participants.