Spacecraft systems collect health-related data continuously, which can give an indication of the systems’ health status. While they rarely occur, the repercussions of such system anomalies, faults, or failures can be severe, safety-critical and costly. Therefore, the data are used to anticipate any kind of anomalous behaviour. Typically this is performed by the use of simple thresholds or statistical techniques. Over the past few years, however, data-driven anomaly detection methods have been further developed and improved. They can help to automate the process of anomaly detection. However, it usually is time intensive and requires expertise to identify and implement suitable anomaly detection methods for specific systems, which is often not feasible for application at scale, for instance, when considering a satellite consisting of numerous systems and many more subsystems. To address this limitation, a generic diagnostic framework is proposed that identifies optimal anomaly detection techniques and data pre-processing and thresholding methods. The framework is applied to two publicly available spacecraft datasets and a real-life satellite dataset provided by the European Space Agency. The results show that the framework is robust and adaptive to different system data, providing a quick way to assess anomaly detection for the underlying system. It was found that including thresholding techniques significantly influences the quality of resulting anomaly detection models. With this, the framework can provide both a way forward in developing data-driven anomaly detection methods for spacecraft systems and guidance relative to the direction of anomaly detection method selection and implementation for specific use cases.