Context: High blood pressure is one of the leading preventable causes of cardiovascular death worldwide. In this regard, several studies have shown interest in the benefits of isometric exercise on blood pressure regulation. Objective: To assess whether low-intensity isometric handgrip exercise (LI-IHE) is an effective strategy to lower blood pressure levels in prehypertensive and hypertensive patients. Data Source: This study was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and registered with PROSPERO. Potentially eligible studies were identified after a systematic search conducted on 4 international databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), PEDro, and SPORTDiscus. Study Selection: We included randomized controlled trials that comprised patients who received LI-IHE. Study Design: Systematic review with meta-analysis. Level of Evidence: Level 3. Data Extraction: Data related to patient characteristics, exercise programs, risk-of-bias assessment, and outcomes of interest were systematically reviewed independently by 2 authors. Results: The following reductions (mean differences) were observed after LI-IHE: systolic blood pressure (SBP), (MD) = −5.43 mm Hg; (95% CI, −8.47 to −2.39; P = 0.0005); diastolic blood pressure (DBP), −2.41 mm Hg (95% CI, −4.33 to −0.48; P = 0.01); mean arterial pressure (MAP), −1.28 mm Hg (95% CI, −2.99 to 0.44; P = 0.14). Conclusion: LI-IHE seems to lower SBP, DBP, and MAP values in prehypertensive and hypertensive adults. It appears that LI-IHE reduces, in greater magnitude, blood pressure levels in hypertensive patients, specifically in patients aged <45 years, those who are overweight, and those on medications. Nevertheless, substantial heterogeneity in the main results and in the analyses by subgroups generated uncertainty about the real reduction magnitude that LI-IHE can produce on blood pressure.