This study examined the differences in quality of life (QoL) between active and sedentary schoolchildren and analyzed these differences by gender and weight status. A total of 1409 children, aged 11-13 years, from 20 schools located in 20 municipalities of the province of Cuenca were invited to participate in a cross-sectional study; 1073 children agreed (76.15% response rate), of which 536 (49.9%) were boys. QoL was measured with Child Health and Illness Profile-Child Edition (CHIP-CE), an instrument measuring children's perception of their own health using a Likert-type scale with five dimensions: satisfaction, comfort, resilience, risk avoidance, and achievement. Multivariate analysis of variance using the scores of the different CHIP-CE dimensions as dependent variables, physical activity, gender, and body mass index (BMI) category as fixed factors, and age as co-variate showed the following: (1) the scores of active children were significantly better than the scores of sedentary children for every dimension except risk avoidance; (2) there were no significant differences in QoL by BMI category; and (3) girls had better mean scores than boys for resilience, risk avoidance, and achievement, and worse scores for comfort. These results suggest that active children have a better QoL and that gender differences favoring boys diminish or even reverse to favor active girls.