The identification of the structural collapse mode is an important foundation of structural anti-collapse design and safety evaluation. The collapse mode evaluation method based on probability reliability is widely used in theoretical research and engineering applications. However, studies on the collapse mode of isolated structures have rarely been reported. For the initial damage, the main control excitation and the remaining system constraints of isolated structures all being different from that of traditional fixed-base structures, the collapse mode and the collapse mechanical behaviors of the isolated structure are disparate from the traditional fixed-base structures. The most likely collapse mode of isolated structures subjected to multi-directional dynamic coupling excitation is evaluated based on reliability theory in the presented research work. First, multi-directional dynamic coupling analysis on the isolated structure is performed. Then, a reliability analysis method suitable for isolated structures is proposed, which takes the damage index as the state parameter, and calculates the failure probability based on the quadratic fourth-order moment theory method. The structural collapse probabilities under different collapse modes are calculated, in order to evaluate the most likely collapse mode of the isolated structure. Finally, the identification method is applied to one prototype isolated structure designed in accordance with the Chinese design code. The results indicate that the identification method based on cumulative damage and reliability theory could effectively be used for evaluation of the most likely collapse mode of the isolated structure.