Aim: To explore the integrated cardiopulmonary, metabolic, and muscular response to incremental exercise in individuals with cerebral palsy (CP) compared with typically developing participants. Method: This was a prospective cross-sectional study. Sixteen (seven male) individuals with CP (classified in Gross Motor Function Classification System levels II–V) and 30 (15 male) typically developing participants performed a treadmill-based incremental submaximal test and an exercise test to task failure. Participants used running frames (CP) or performed traditional running (typically developing participants). Metabolic and cardiopulmonary parameters were measured during both tests. Electromyography of the vastus lateralis and gastrocnemius medialis was recorded during the test to task failure. Results: Compared with typically developing participants, individuals with CP showed decreased minute ventilation (p < 0.05), increased respiratory frequency at a comparable exercise intensity (p < 0.05), and an altered metabolic response, on the basis of the partial pressure of carbon dioxide (p < 0.05) and lactate levels (p < 0.001), during both tests. In addition, participants with CP exhibited a lower ventilatory efficiency during the test to task failure (p < 0.01). Electromyography analysis suggested peripheral skeletal muscle fatigue in the lower limbs (p < 0.05) in individuals with CP compared with typically developing participants. Interpretation: Individuals with CP have a disproportional ventilatory response to incremental exercise, not driven by metabolic perturbations. The increased breathing frequency resulted in high rate of perceived exertion and signs of peripheral muscle fatigue compared with typically developing participants. Our findings stress the importance of interventions focused on ventilatory function in individuals with CP.