The development of high-entropy alloys (HEAs) comprising multiple principal components is an innovative design strategy for metallic materials from the perspective of thermodynamic entropy. However, despite their potential candidacy for engineering applications, the lack of research on the cyclic loading responses as well as constitutive modeling of the HEAs is a major constraint. Therefore, the present work focuses on the cyclic plasticity of a typical carbon-doped interstitial HEA (iHEA) with nominal composition Fe49.5Mn30Co10Cr10C0.5 (at.%). The results of stress-controlled cyclic tests with nonzero mean stress showed that the iHEA exhibits significant cyclic hardening and stress level–dependent ratcheting. Owing to its improved cyclic hardening, the saturated ratcheting strain rate of the iHEA is lower than that of conventional steels such as the 316L stainless steel. Furthermore, microscopic characterizations revealed that the cyclic deformations caused massive martensitic phase transformation and hierarchical structures in the iHEA. The experimental results were used to develop a physical mechanism-based crystal plasticity constitutive model that is capable of describing the cyclic plasticity of the iHEA, which was implemented into a finite element framework. The simulation results showed that the loading stress significantly affected the microstructural evolutions, leading to a stress level–dependent cyclic plasticity. Thus, this investigation provides a fundamental basis for fatigue tests and service life prediction/optimization of the iHEA in the future, which can promote its engineering applications.