Vitamin D and calcium insufficiency has been related to elevated blood pressure (BP) and cardiovascular complications. This systematic review and meta-analysis investigates the effect of calcium and vitamin D co-supplementation on BP. A systematic search was conducted of electronic databases, including Web of Sciences, MEDLINE, Scopus, EMBASE, and the Cochrane Library, along with searches of gray literature and reference lists from included trials. There were no language restrictions, and the databases were searched from inception to October 2019. Randomized controlled trials, using calcium and vitamin D co-supplementation and reporting mean systolic BP and/or diastolic BP (DBP) with SDs, were included in the systematic review. Articles were evaluated independently by 2 researchers based on inclusion and exclusion criteria. A random effects model was conducted to synthesize the data. Eight trials were included in the meta-analysis. Meta-analysis of these 8 trials indicated a nonsignificant reduction in systolic BP in the calcium and vitamin D co-supplementation group compared with control (standardized mean difference, -0.23; 95% CI, -0.52 to 0.06). Conversely, there was a statistically significant decrease in DBP (standardized mean difference, -0.29; 95% CI, -0.55 to -0.02). Subgroup analysis suggested that young adults achieve a greater reduction in DBP than other age groups. Calcium and vitamin D co-supplementation can modulate DBP and should be investigated more specifically in large, well-designed trials of hypertensive populations. (Clin Ther. 2020;42:XXX-XXX) © 2020 Elsevier HS Journals, Inc.