Abstract Background Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with limited robust disease-modifying therapies presently available. While several treatments are aimed at improving health-related quality of life (HRQoL), longitudinal data on how QoL changes across the disease course are rare. Objectives To explore longitudinal changes in emotional well-being and HRQoL in ALS. Methods Of the 161 subjects initially recruited, 39 received 2 subsequent follow-up assessments at 6 and 12 months after baseline. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess physical impairment. HRQoL was assessed using the ALS Assessment Questionnaire (ALSAQ-40). The D50 disease progression model was applied to explore longitudinal changes in HRQoL. Results Patients were primarily in the early semi-stable and early progressive model-derived disease phases. Non-linear correlation analyses showed that the ALSAQ-40 summary index and emotional well-being subdomain behaved differently across disease phases, indicating that the response shift occurs early in disease. Both the ALSFRS-R and ALSAQ-40 significantly declined at 6- and 12-monthly follow-ups. Conclusion ALSAQ-40 summary index and emotional well-being change comparably over both actual time and model-derived phases, indicating that the D50 model enables pseudo-longitudinal interpretations of cross-sectional data in ALS.