In clinical scenarios, the use of biomedical sensors, devices and multi-parameter assessments is fundamental to provide a comprehensive portrait of patients’ state, in order to adapt and personalize rehabilitation interventions and support clinical decision-making. However, there is a huge gap between the potential of the multidomain techniques available and the limited practical use that is made in the clinical scenario. This paper reviews the current state-of-the-art and provides insights into future directions of multi-domain instrumental approaches in the clinical assessment of patients involved in neuromotor rehabilitation. We also summarize the main achievements and challenges of using multi-domain approaches in the assessment of rehabilitation for various neurological disorders affecting motor functions. Our results showed that multi-domain approaches combine information and measurements from different tools and biological signals, such as kinematics, electromyography (EMG), electroencephalography (EEG), near-infrared spectroscopy (NIRS), and clinical scales, to provide a comprehensive and objective evaluation of patients’ state and recovery. This multi-domain approach permits the progress of research in clinical and rehabilitative practice and the understanding of the pathophysiological changes occurring during and after rehabilitation. We discuss the potential benefits and limitations of multi-domain approaches for clinical decision-making, personalized therapy, and prognosis. We conclude by highlighting the need for more standardized methods, validation studies, and the integration of multi-domain approaches in clinical practice and research.