Smart biosensors attract significant interest due to real-time monitoring of user health status, where bioanalytical electronic devices designed to detect various activities and biomarkers in the human body have potential applications in physical sign monitoring and health care. Bioelectronics can be well integrated by output signals with wireless communication modules for transferring data to portable devices used as smart biosensors in performing real-time diagnosis and analysis. In this review, the scientific keys of biosensing devices and the current trends in the field of smart biosensors, (functional materials, technological approaches, sensing mechanisms, main roles, potential applications and challenges in health monitoring) will be summarized. Recent advances in the design and manufacturing of bioanalytical sensors with smarter capabilities and enhanced reliability indicate a forthcoming expansion of these smart devices from laboratory to clinical analysis. Therefore, a general description of functional materials and technological approaches used in bioelectronics will be presented after the sections of scientific keys to bioanalytical sensors. A careful introduction to the established systems of smart monitoring and prediction analysis using bioelectronics, regarding the integration of machine-learning-based basic algorithms, will be discussed. Afterward, applications and challenges in development using these smart bioelectronics in biological, clinical, and medical diagnostics will also be analyzed. Finally, the review will conclude with outlooks of smart biosensing devices assisted by machine learning algorithms, wireless communications, or smartphone-based systems on current trends and challenges for future works in wearable health monitoring.