Machine and deep learning techniques are fuelling a revolution in the health domain and are attracting the interest of many cross-disciplinary research groups all over the world. The Special Issue “Advances in Machine and Deep Learning in the Health Domain” focuses on original research covering novel theories, methods, algorithms, architectures, and applications related to areas of machine and deep learning applied to the health domain. As is known, machine and deep learning deal with data with the goal of extracting information and related knowledge that is hidden within to make predictions and, subsequently, decisions. The list of topics related to this Special Issue was quite wide, covering issues related to artificial intelligence and machine learning, with reference to their application in, among other areas, knowledge management, data mining, decision support systems, precision medicine, healthcare systems, image and signal processing, sensors, and biomedical applications.The response from the international scientific community has been very positive, and the number of papers submitted indicates the large appeal of the topics concerned. The review process was thorough, accepting only 17 manuscripts of high quality and showing a wide variety of the topics discussed.