This study aimed to examine the effects of an adapted physical activity (APA) intervention on health-related physical fitness (HRPF) in adolescents with intellectual disability (ID). With a randomized controlled trial design, adolescents aged 12–18 years, with mild and moderate ID, and being overweight and obese were recruited and randomly assigned to either an intervention or a control group. The APA intervention consisted of overall moderate intensity aerobic and resistance exercise, with a duration of 45 min/session, a frequency of 2 sessions/week, and lasting for 9 months. A negative control was involved, in which participants received no treatment. Changes in four fitness tests, including the 9-min run/walk, handgrip strength, 30-s sit-ups, and sit-and-reach tests, were assessed between the groups using general linear models. A total of 57 participants (39 in the intervention group and 18 in the control group) completed the study. Significant mean differences in changes in the 9-min run/walk test (413.6 m [95% CI 146.72 m, 680.41 m], p = 0.003) and the right-side sit-and-reach test (2.2 cm [95% CI 0.37 cm, 4.09 cm], p = 0.020) respectively were observed in the intervention group, compared to the control group. No significant between-group improvement was observed for the handgrip strength and the 30-s sit-ups tests. The APA intervention induced beneficial effects on cardiorespiratory fitness and potential beneficial effects on flexibility for adolescents with ID. However, no significant effects of this intervention on muscular strength and endurance were observed in this study. Future studies should consider involving effective exercises in interventions to improve muscular strength and endurance. Copyright © 2022 The Author(s).