This invention provides a system and method for runtime determination (self-diagnosis) of camera miscalibration (accuracy), typically related to camera extrinsics, based on historical statistics of runtime alignment scores for objects acquired in the scene, which are defined based on matching of observed and expected image data of trained object models. This arrangement avoids a need to cease runtime operation of the vision system and/or stop the production line that is served by the vision system to diagnose if the system's camera(s) remain calibrated. Under the assumption that objects or features inspected by the vision system over time are substantially the same, the vision system accumulates statistics of part alignment results and stores intermediate results to be used as indicator of current system accuracy. For multi-camera vision systems, cross validation is illustratively employed to identify individual problematic cameras. The system and method allows for faster, less-expensive and more-straightforward diagnosis of vision system failures related to deteriorating camera calibration.