There is a lack of reliable, repeatable, and non-invasive clinical endpoints when investigating treatments for intellectual disability (ID). The aim of this study is to explore a novel approach towards developing new endpoints for neurodevelopmental disorders, in this case for ARID1B-related ID. In this study, twelve subjects with ARID1B-related ID and twelve age-matched controls were included in this observational case–control study. Subjects performed a battery of non-invasive neurobehavioral and neurophysiological assessments on two study days. Test domains included cognition, executive functioning, and eye tracking. Furthermore, several electrophysiological assessments were performed. Subjects wore a smartwatch (Withings® Steel HR) for 6 days. Tests were systematically assessed regarding tolerability, variability, repeatability, difference with control group, and correlation with traditional endpoints. Animal fluency, adaptive tracking, body sway, and smooth pursuit eye movements were assessed as fit-for-purpose regarding all criteria, while physical activity, heart rate, and sleep parameters show promise as well. The event-related potential waveform of the passive oddball and visual evoked potential tasks showed discriminatory ability, but EEG assessments were perceived as extremely burdensome. This approach successfully identified fit-for-purpose candidate endpoints for ARID1B-related ID and possibly for other neurodevelopmental disorders. Next, results could be replicated in different ID populations or the assessments could be included as exploratory endpoint in interventional trials in ARID1B-related ID.