Objective <p>Handgrip strength is a robust biological health biomarker in children and adolescents. To estimate the mediating effect of body mass index and lifestyles on the relation between sociodemographic characteristics and handgrip strength in Colombian children and adolescents.</p> Methods <p>This is a cross-sectional analysis with a sample of 2647 young people. HGS was evaluated with a TKK 5101 digital dynamometer (Takei Scientific Instruments Co., Ltd., Tokyo, Japan). Relative handgrip strength was estimated in kilograms. Two independent structural equation models were developed. They included sociodemographic variables, lifestyles, body mass index, and absolute or relative HGS. Models were estimated by weighted least squares mean and variance adjustment (WLSMV). RMSEA, TLI, and CFI were determined to assess model goodness of fit. Direct, indirect, and total effects were evaluated, as well as the mediation percentage in the different association pathways.</p> Results <p>An effect mediated by physical activity levels was detected in the relation between sex and two handgrip strength indicators (absolute HGS 3.47% and relative HGS 1.85%). In the relation between age and absolute HGS, a mediation of 2.61% was found through body mass index and a mediation of 0.52% through physical activity levels and body mass index. In the relation between physical activity levels and relative HGS, a 37.50% mediation was found through body mass index.</p> Conclusions <p>Two mediating effects stand out: physical activity levels are mediators in the relation between sex and two handgrip strength indicators. In addition, body mass index is a mediating variable in the relation between physical activity levels and relative HGS.</p>