In this paper, a class of nonlinear systems with mismatched disturbance and actuator failure is investigated. A disturbance observer is proposed to estimate the disturbance first and the error of the estimation converges to zero exponentially. By introducing an integral sliding mode surface, the disturbance observer-based integral sliding mode fault tolerant control scheme is proposed to attenuate the disturbance and guarantee the stability of the system. In particular, the control law is designed for decoupling the partial disturbance and attenuating the disturbance that cannot be decoupled. Finally, two examples are given to illustrate the effectiveness of the proposed method.