Abstract: High-entropy alloy has become a research hotspot because of its unique microstructure and mechanical properties. The appearance of high-entropy alloy breaks the design concept of traditional alloy with one or two elements as the main element and other elements as the auxiliary element, providing a broader space for the development of new materials. Conventional alloys are generally optimized by four different strengthening methods, as are high-entropy alloys consisting of five or more elements. Appropriately doped interstitial atoms with small atomic sizes (such as C, B, O, and N) can dissolve into crystal interstice, combine with alloying elements to form a fine microstructure and dispersion-strengthened phase, and improve the properties of high-entropy alloy by reducing the layer fault energy and changing the dislocation motion mode. Therefore, exploring the effect of interstitial atom doping on the properties of high-entropy alloys is conducive to promoting the application of high-entropy alloys in different material fields. The effects of the interstitial atoms C, N, O, and B on the microstructures and properties of high-entropy alloys are analyzed. The contents of four kinds of interstitial atoms and their effects on the microstructures and properties of high-entropy alloys are summarized. Numerous studies have shown that doping interstitial atoms can not only regulate the structural composition of the phase (i.e., promote/inhibit the phase transformation and precipitate the second phase particles) in high-entropy alloy systems. The deformation mechanism, i.e., TWIP (Twinning induced plasticity) and TRIP（Transformation induced plasticity) effects, can also be changed to strengthen and toughen the material. Its effective utilization can not only broaden the design idea of high-entropy alloy but also effectively reduce the preparation cost of aviation materials. Finally, a new direction in microstructure design of high-strength, high-toughness, and high-entropy alloys containing interstitial atoms is proposed to (1) understand the doping mechanism of different types of high-entropy alloys and establish a solution-strengthening model more suitable for high-entropy alloy systems and (2) determine the appropriate interstitial atoms and doping amount to adjust the microstructures and mechanical properties of high-entropy alloys. The study and design of high-entropy alloys doped with different interstitial atoms are expected to reveal the effects of different interstitial atoms on the phase structure, deformation mechanism, and mechanical properties, which have important scientific and engineering practical significance.