Abstract: The risk assessment of high-rise building fires is crucial for ensuring the safety of personnel and reducing property damage. Traditional assessment methods have limitations and cannot comprehensively and systematically identify the key causative factors and their interactions of fire risk. Therefore, this study proposes a fire risk assessment method based on the Interpretive Structural Model (ISM) and Bayesian Network (BN), aiming to more accurately evaluate the fire risk of high-rise buildings. This study first starts from the causes of fire disasters and establishes a high-rise building fire risk assessment index system based on classical accident causation theory, which includes four secondary factors such as electrical factors, fire protection systems, building environment, and fire management, as well as 22 tertiary factors. Subsequently, the direct impact relationship of ISM on fire risk was analyzed, and a layered structure for high-rise building fires was constructed. Based on this, a BN model was mapped and an ISM-BN fire risk analysis model was established. Finally, sensitivity analysis, forward reasoning, and backward reasoning are conducted on the ISM-BN model to identify key disaster causing factors that affect the risk of high-rise building fires, and corresponding countermeasures are proposed. The results indicate that through model analysis, the key factors leading to the risk of high-rise building fires are identified as the smoke control system S8, fire water supply and hydrant system S9, electrical equipment S3, and safety evacuation S17. Especially when the smoke control system malfunctions, the probability and risk of fire occurrence significantly increase. The ISM-BN model proposed in this study can effectively identify the key disaster causing factors and their influencing mechanisms of high-rise building fire risk. Based on the analysis results, targeted fire risk prevention and control measures have been proposed, providing theoretical basis and decision support for improving the fire safety management level of high-rise buildings.