This study aimed to examine the causal relationship between systolic blood pressure (SBP) and myocardial injury (MI), and to evaluate its prognostic implications for all-cause and cardiovascular mortality. A two-stage analytical approach was used. First, Mendelian randomization (MR) was conducted to assess the independent causal effects of SBP on six MI-related phenotypes, with adjustment for potential confounders, including lipid profiles, glycemic indices, and anthropometric traits. Second, data from 4459 participants in the National Health and Nutrition Examination Survey, with a follow-up period of up to 15 years, were analyzed. The dose-response relationship between SBP and MI was assessed using restricted cubic spline analysis. Thresholds based on sex-, age-, and comorbidities were identified using the Johnson-Neyman interaction model. MR analysis demonstrated a causal association between elevated SBP and increased risks of acute heart failure (odds ratio [OR] = 1.523), MI (OR = 1.014), and ischemic stroke (OR = 33.339). In the prospective group analysis, SBP ≥ 180 mmHg was associated with a 213.4% increased risk of MI (OR = 3.134, p = 0.003), and a graded increase in mortality was observed (hazard ratio [HR] = 2.783 for all-cause death; HR = 1.888 for cardiovascular death). Sex-stratified analysis demonstrated that the lowest MI risk occurred at SBP levels of 120-150 mmHg in men and extended to 162 mmHg in women. Among individuals aged ≥ 43 years, the risk of all-cause mortality significantly increased when SBP exceeded 135 mmHg (p < 0.001). A U-shaped relationship between SBP and mortality was observed in individuals aged ≥ 58 years with MI, with the lowest risk at 113 mmHg. Genetic and observational evidence support a causal role of elevated SBP in the development of MI. The findings demonstrate sex- and age-specific thresholds, along with a U-shaped mortality curve, providing a nuanced framework for individualized blood pressure management strategies.