Purpose: To identify Health-related Quality of Life (HR-QoL) trajectories in a large heterogeneous cohort of people with a physical disability and/or chronic disease during and after rehabilitation and to determine which factors before discharge are associated with longitudinal trajectory membership. Methods: A total of 1100 people with a physical disability and/or chronic disease were included from the longitudinal cohort study Rehabilitation, Sports and Active lifestyle. All participants participated in a physical activity promotion programme in Dutch rehabilitation care. HR-QoL was assessed using the RAND-12 Health Status Inventory questionnaire at baseline (T0: 3–6 weeks before discharge) and at 14 (T1), 33 (T2) and 52 (T3) weeks after discharge from rehabilitation. A data-driven approach using Latent Class Growth Mixture modelling was used to determine HR-QoL trajectories. Multiple binomial multivariable logistic regression analyses were used to determine person-, disease- and lifestyle-related factors associated with trajectory membership. Results: Three HR-QoL trajectories were identified: moderate (N = 635), high (N = 429) and recovery (N = 36). Trajectory membership was associated with person-related factors (age and body mass index), disease-related factors (perceived fatigue, perceived pain and acceptance of the disease) and one lifestyle-related factor (alcohol consumption) before discharge from rehabilitation. Conclusions: Most of the people who participated in a physical activity promotion programme obtained a relatively stable but moderate HR-QoL. The identified HR-QoL trajectories among our heterogeneous cohort are disease-overarching. Our findings suggest that people in rehabilitation may benefit from person-centred advice on management of fatigue and pain (e.g. activity pacing) and the acceptance of the disability.