A new approach to the design of nonlinear disturbance observers (DOBs) for a class of nonlinear systems described by input–output differential equations is presented in this paper. In contrast with established forms of nonlinear DOBs, the most important feature of this new type of DOB is that only measurement of the output variable is required, rather than the state variables. An inverse simulation model is first constructed based on knowledge of the structure and parameters of a conventional model of the system. The disturbance can then be estimated by comparing the output of the inverse model and the input of the original nonlinear system. Mathematical analysis demonstrates the convergence of this new form of nonlinear DOB. The approach has been applied to disturbance estimation for a linear system and a new form of linear DOB has been developed. The differences between the proposed linear DOB and the conventional form of frequency-domain DOB are discussed through a numerical example. Finally, the nonlinear DOB design method is illustrated through an application involving a simulation of a jacketed continuous stirred tank reactor system.