Longitudinal tracking of multiple sclerosis (MS) symptoms in an individual’s environment may improve self-monitoring and clinical management for people with MS. We aimed to develop and evaluate a machine learning (ML)–based digital phenotyping approach to monitor the severity of clinically-relevant MS symptoms. We used passive sensing data to predict short-term fluctuations in patient-reported symptoms, including depressive symptoms, global MS symptom burden, severe fatigue, and poor sleep quality. We conducted a 12- to 24-week longitudinal study involving 104 people with MS, collecting passive sensor and behavioral health data. Smartphone sensors recorded call activity, location, and screen use, while fitness trackers captured heart rate, sleep patterns, and step count. Our algorithm predicted depressive symptoms with an accuracy of 80.6% (F1-score=0.76), high global MS symptom burden with an accuracy of 77.3% (F1-score=0.78), severe fatigue with an accuracy of 73.8% (F1-score=0.74), and poor sleep quality with an accuracy of 72.0% (F1-score=0.70). Our digital phenotyping approach using passive sensors on smartphones and fitness trackers may help patients with real-world, continuous self-monitoring of common symptoms in their own environment and assist clinicians with better triage of patient needs for timely interventions in MS and potentially other chronic neurological disorders.