Hypertension-related death is the leading cause of mortality worldwide, making blood pressure (BP) control an important issue. Salt substitute is a non-pharmaceutical strategy to improve hypertension control. The goal of this study was to evaluate the effect of salt substitute on BP and cardiovascular disease. The authors searched the Cochrane Library and PubMed databases through March 2022, and assessed the risk-of-bias for included studies by the Cochrane risk-of-bias tool. Twenty-three randomized controlled trials with 32073 patients were included in our systematic review. A meta-analysis with random effects was performed to analyze the effects of salt substitute on systolic and diastolic BP, 24-h urinary sodium and potassium, and cardiovascular and all-cause mortality. In the random-effects model, participants consuming salt substitute showed significant reduction in systolic BP (mean difference (MD) −4.80 mmHg, 95% confidence interval (CI) −6.12 to −3.48, P < 0.0001) and diastolic BP (MD −1.48 mmHg, 95% CI −2.06 to −0.90, P < 0.0001) compared with participants consuming normal salt. In the urine electrolyte analysis, the salt substitute group had significant reduction in 24-h urine sodium (MD −22.96 mmol/24-h, P = 0.0001) and significant elevation in 24-h urine potassium (MD 14.41 mmol/24-h, P < 0.0001). Of the five studies with mortality outcome data, salt substitute significantly reduced all-cause mortality (hazard ratio 0.88, P = 0.0003). In conclusion, our analyses showed that salt substitute has a strong effect on lowering BP and reducing all-cause mortality. By modifying the daily diet with salt substitute, the authors can improve BP control by using this non-pharmaceutical management.