Objective: To evaluate the effect of a lifestyle intervention on fatigue, participation, quality of life, gross motor functioning, motivation, self-efficacy and social support, and to explore mediating effects of physical behavior and physical fitness. Design: A randomized controlled trial with intention to treat analysis. Setting: Rehabilitation centers in university hospitals in the Netherlands. Subjects: Adolescents and young adults with spastic cerebral palsy. Interventions: A six-month lifestyle intervention that consisted of physical fitness training combined with counseling sessions focused on physical behavior and sports participation. Main measures: Fatigue, social participation, quality of life and gross motor functioning. Results: The lifestyle intervention was effective in decreasing fatigue severity during the intervention (difference = -6.72, p = 0.02) and in increasing health-related quality of life with respect to bodily pain (difference = 15.14, p = 0.01) and mental health (difference = 8.80, p = 0.03) during follow-up. Furthermore, the domain participation and involvement of the social support increased during both the intervention (difference = 5.38, p = 0.04) and follow-up (difference = 4.52, p = 0.03) period. Physical behavior or physical fitness explained the observed effects for 22.6%, 9.7% and 28.1% of improvements on fatigue, bodily pain and mental health, but had little effect on social support (2.6%). Interpretation: Fatigue, bodily pain, mental health and social support can be improved using a lifestyle intervention among adolescents and young adults with cerebral palsy. Furthermore, substantial mediating effects were found for physical behavior and physical fitness on fatigue, bodily pain and mental health.