The conducted study is devoted to the research area of control of high speed flows and shock-wave configurations. Experimental and numerical results on the interaction of a plane shock wave (M = 5–6) with the area formed by ionization instability in gas discharge plasma at a pressure of 3–7 Torr and gas-discharge current of 100–400 mA are presented. The region of ionization instability in plasma of high degree of ionization and non-equilibrium (gas temperature T ∼ 300–600 K, electron temperature Te∼5⋅103 K) has been obtained experimentally in air. This instability is characterized by spherical strata of changing shape. Two types of a shape of the ionization instability have been obtained: large-scale type and small-scale type. Also, the transitional type from large-scaled strata to low-scaled ones has been obtained. The influence of the ionization instability was established to cause the distortion of an initially plane shock wave up the complete disappearance of its front. Numerical modeling the interaction of the initially plane shock wave with ionization-unstable plasma using the Euler system of equations has been conducted. The area formed by ionization unstable plasma was modeled via a set of thermal layers with varying densities (and temperatures). Changing the physical–chemical properties of the gas medium was taken into account varying the ratio of specific heats. Layered structures with wavy shock-wave and contact discontinuity fronts have been observed. The multiple generations of shear layer instabilities and the Richtmyer–Meshkov instabilities have been obtained as the result of the interaction of a shock wave with thermal strata. It has confirmed that the shapes of the both discontinuities change acquiring an unstable character. Examples of the flow modes with the disappearance of the shock wave front causing by the origination of a structure with cellular order of shear layer instabilities have been presented. A good agreement at the qualitative level with the experimental Schlieren images has been demonstrated.