In this paper, an isogeometric analysis (IGA) framework based on the high-order sandwich plate theory is developed for the first time to deal with both buckling and wrinkling problems of variable-stiffness sandwich plates under compression. The present sandwich plate model is formulated based on the extended high-order sandwich plate theory (EHSAPT). The weak-form governing equations are firstly derived from the principle of virtual work, and afterward the IGA formulations based on the Non-Uniform Rational B-Splines (NURBS) are applied to predict the instability loads and the corresponding instability modes. Both the membrane and non-membrane conditions are integrated into the linear buckling analysis. The novelty of this work lies in that the employment of high-order continuous NURBS basis functions can directly fulfill the [Formula: see text] continuity requirement inherent in the EHSAPT theory, which enables the EHSAPT-based IGA model to be formulated with fewer degrees of freedom. Besides, the developed EHSAPT-based IGA model has also the ability to capture the overall buckling or wrinkling modes of the sandwich plates. The accuracy and effectiveness of the proposed EHSAPT-based IGA model are verified by comparison with previously published results and those obtained using ABAQUS. Effects of the core thickness and fiber angle on the buckling behaviors of the sandwich plates are also studied in numerical examples. It is observed that the non-uniform in-plane pre-stress over the skin layers is the main reason for the non-periodic wrinkling of constant-stiffness sandwich constructions, whereas the non-uniformity of both the in-plane pre-stress and out-of-plane bending stiffness is responsible for the non-periodic wrinkling of variable-stiffness sandwich constructions. The results presented herein may be beneficial for the design of variable-stiffness sandwich constructions under compression.