Abstract: High-entropy alloys (HEAs) possess outstanding features such as corrosion resistance, irradiation resistance, and good mechanical properties. A few HEAs have found applications in the fields of aerospace and defense. Extensive studies on the deformation mechanisms of HEAs can guide microstructure control and toughness design, which is vital for understanding and studying state-of-the-art structural materials. Synchrotron X-ray and neutron diffraction are necessary techniques for materials science research, especially for in situ coupling of physical/chemical fields and for resolving macro/microcrystallographic information on materials. Recently, several researchers have applied synchrotron X-ray and neutron diffraction methods to study the deformation mechanisms, phase transformations, stress behaviors, and in situ processes of HEAs, such as variable-temperature, high-pressure, and hydrogenation processes. In this review, the principles and development of synchrotron X-ray and neutron diffraction are presented, and their applications in the deformation mechanisms of HEAs are discussed. The factors that influence the deformation mechanisms of HEAs are also outlined. This review focuses on the microstructures and micromechanical behaviors during tension/compression or creep/fatigue deformation and the application of synchrotron X-ray and neutron diffraction methods to the characterization of dislocations, stacking faults, twins, phases, and intergrain/interphase stress changes. Perspectives on future developments of synchrotron X-ray and neutron diffraction and on research directions on the deformation mechanisms of novel metals are discussed.