The attitude tracking control problem of flexible spacecraft subjected to parameter uncertainties, time-dependent external disturbances, actuator input nonlinearity, and input actuator misalignment is investigated in this paper. Explicitly, the proposed strategy addresses the input actuator misalignment and dead-zone issues that increase the controller design difficulties. Initially, a new second-order sliding mode observer (SoSMO) using an extended state approach is developed by adding a correction function to improve observer performance to estimate unwanted system perturbations. Then, a distinct SoSMO-based integral-type sliding mode control (ISMC) structure is designed in a unified manner to guarantee the asymptotic stability of the closed-loop system. Comparative numerical simulations under input actuator misalignment, the dead-zone nonlinearity, external disturbance, and inertia uncertainty are performed to illustrate the effectiveness of the proposed controller.