A novel method for designing Disturbance Observer (DOB), an essential component of Active Anti-Disturbance Control (AADC) schemes, for nonlinear Multiple Input Multiple Output (MIMO) systems has been proposed. In contrast to the prevailing observer gain based approach, the proposed DOB design methodology employs the MIMO “Hirschorn Inverse” technique. The overall architecture and the related design pragmatics have been discussed. Feasibility and disturbance estimation performance of the proposed approach have been illustrated by a Quadruple Tank process with two inputs and two outputs.