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Objective: To explore the association between genetic variants of matrix metalloproteinase enzyme 2 (MMP2) gene and the blood pressure of children and adolescents. Methods: This cross-sectional study was performed in 2016 and included 4 155 children and adolescents in the urban area of Guangzhou. Physical examinations (including body height, weight, and blood pressure), questionnaires (including general characteristics, physical exercise, parental educational level, household income, etc.), and blood sampling were performed. Multivariable linear regression models were used to investigate the associations of MMP2 genetic variations (rs243865, rs7201) and the genetic risk score (GRS) level with standardized blood pressure. Mediating effect of standardized body mass index (BMI) was further assessed by process analysis in the association between GRS level and blood pressure, and potential additive interaction between physical activity and GRS level was analyzed using the product term in the regression model. Results: A total of 4 155 primary and secondary schoolchildren were finally included in the analysis, consisting of 1 401 (33.7%) second grade pupils of primary school, 1 422 (34.2%) first grade pupils of middle school, and 1 332 (32.1%) first-grade students of senior high school. After adjusting for age, sex, parental educational level, and family income, as compared to the rs243865 TT genotype, the CC/CT genotype increased diastolic blood pressure (DBP) by 0.461 standard deviations ( SD ) ( β for dominant model=0.461, 95% CI 0.199-0.723). When compared to the rs7201 CC genotype, the AA/AC genotype showed 0.147 SD higher systolic blood pressure (SBP) ( β for recessive model=0.147, 95% CI 0.014-0.279) and 0.171 SD increased DBP ( β for recessive model=0.171, 95% CI 0.039-0.304). For each increment of GRS level, SBP and DBP increased by 0.151 SD ( β for dominant model=0.151, 95% CI 0.029-0.272) and 0.242 SD ( β =0.242, 95% CI 0.120-0.363), respectively. The mediating effect of BMI accounted for 28.3% and 12.6% of the total effect of GRS on SBP and DBP, respectively. After controlling BMI, the direct effect of GRS on DBP remained statistically significant ( P <0.001). The insufficient moderate-to-vigorous physical activity (<0.5 h/d) showed a significant interaction with GRS on SBP under additive scale ( β for interaction=0.518, 95% CI 0.088-0.949, P =0.018). Conclusions: rs243865 and rs7201 variants in MMP2 gene are associated with the elevated blood pressure of children and adolescents. Obesity may yield a mediation role in the associations, while insufficient physical activity may have a positively additive interaction with MMP2 genetic variants.