High blood pressure (BP) is a global health challenge. Isometric resistance training (IRT) has demonstrated antihypertensive effects, but safety data are not available, thereby limiting its recommendation for clinical use. We conducted a systematic review of randomized controlled trials comparing IRT to controls in adults with elevated BP (systolic ≥130 mmHg/diastolic ≥85 mmHg). This review provides an update to office BP estimations and is the first to investigate 24-h ambulatory BP, central BP, and safety. Data were analyzed using a random-effects meta-analysis. We assessed the risk of bias with the Cochrane risk of bias tool and the quality of evidence with GRADE. Twenty-four trials were included (n = 1143; age = 56 ± 9 years, 56% female). IRT resulted in clinically meaningful reductions in office systolic (–6.97 mmHg, 95% CI –8.77 to –5.18, p < 0.0001) and office diastolic BP (–3.86 mmHg, 95% CI –5.31 to –2.41, p < 0.0001). Novel findings included reductions in central systolic (–7.48 mmHg, 95% CI –14.89 to –0.07, p = 0.035), central diastolic (–3.75 mmHg, 95% CI –6.38 to –1.12, p = 0.005), and 24-h diastolic (–2.39 mmHg, 95% CI –4.28 to –0.40, p = 0.02) but not 24-h systolic BP (–2.77 mmHg, 95% CI –6.80 to 1.25, p = 0.18). These results are very low/low certainty with high heterogeneity. There was no significant increase in the risk of IRT, risk ratio (1.12, 95% CI 0.47 to 2.68, p = 0.8), or the risk difference (1.02, 95% CI 1.00 to 1.03, p = 0.13). This means that there is one adverse event per 38,444 bouts of IRT. IRT appears safe and may cause clinically relevant reductions in BP (office, central BP, and 24-h diastolic). High-quality trials are required to improve confidence in these findings. PROSPERO (CRD42020201888); OSF (https://doi.org/10.17605/OSF.IO/H58BZ).