Continuous real-time monitoring of physiological parameters can yield insights into the underlying aspects of many diseases and guide diagnostic and therapeutic decisions in surgeries and for critical care patients. Tissue oxygenation is one of the key physiological parameters and a critical determinant of organ function. Existing systems for monitoring deep-tissue oxygenation are limited by a few factors, including the need for wired connections, the inability to provide real-time data or operation restricted to surface tissues. We demonstrate the first minimally invasive ultrasonic wireless system to monitor deep-tissue O2 that avoids all these drawbacks. The system is composed of a millimeter-sized O2 sensor implant that communicates bi-directionally and digitally with an external transceiver outside the body, enabling deep-tissue O2 monitoring for surgical or critical care indications. The implant is based on integrated circuit and microsystems technologies that enable extreme miniaturization with advanced performance. Furthermore, the system includes a novel wireless power/data transmission strategy that enables the operation of the implant at centimeter-scale depths (up to 10 cm) in tissue. Overall, this technology represents a new class of monitoring and diagnostic system particularly suitable for organ monitoring, as well as other surgical or critical care situations.