Background: Based on Mayer and Salovey's model of emotional intelligence, this study examined whether perceived stress mediates the interplay of emotional intelligence and life satisfaction for girls and boys during early and middle adolescence. Methods: Using multigroup structural equation modeling with questionnaire data from a sample of Spanish adolescent students (N = 800; M[subscript Age]T1 = 14.02, M[subscript Age]T2 = 15.00, SD = 1.21) in 2 waves (T1 = March 2015; T2 = December 2015). Results: Results of multigroup structural equation modeling indicated no group differences between boys and girls in early adolescence (7th and 8th grade) and middle adolescence (9th and 10th grade), as stress function as mediator between emotional intelligence and life satisfaction for all groups. However, latent mean comparison indicated that girls not only perceive and understand emotions better than boys, but they also perceive higher amounts of stress at an older age. Conclusion: Results indicate the potential risk of perceived stress that might drop the protective effect of emotional intelligence on life satisfaction. These findings have implications for future research and educational practice considering combined prevention programs for adolescent's health and well-being.