The nonlinearity and cross-axis coupling of piezo-driven multiple-degree-of-freedom (multi-DOF) nanopositioning systems impose challenges to achieving precise and reliable motion control. This paper develops a new adaptive reliable control approach for a 2-DOF piezoelectric nanopositioning system utilizing a fuzzy back-stepping strategy. First, a virtual tracking model is constructed to address the stabilization problem via a system transformation method. Then, a fuzzy logical system (FLS) model is introduced to mitigate the effects of hysteresis and unmodeled high-order nonlinearity. To obtain high-precision motion tracking with high reliability, the approximation of the unknown piezoelectric actuator's efficiency factor is injected into the reliable controller of nanopositioning systems. Furthermore, an adaptive mechanism based on tracking errors is designed to adjust control parameters automatically to improve the robustness to unknown perturbations. Simulation and practical experiment examples are presented to show the effectiveness and potential of the developed fuzzy reliable nanopositioning control method over existing control approaches.