Systems and methods are disclosed for using patient specific anatomical models and physiological parameters to estimate perfusion of a target tissue to guide diagnosis or treatment of cardiovascular disease. One method includes receiving a patient-specific vessel model and a patent-specific tissue model of a patient anatomy; extracting one or more patient-specific physiological parameters (e.g. blood flow, anatomical characteristics, image characteristics, etc.) from the vessel or tissue models for one or more physiological states of the patient; estimating a characteristic of the perfusion of the patient-specific tissue model (e.g., via a trained machine learning algorithm) using the patient-specific physiological parameters; and outputting the estimated perfusion characteristic to a display.