Low-cycle fatigue behavior of high-entropy alloy (HEAs) and medium-entropy alloys (MEAs) have rarely been reported in literature though it is critical for industrial applications. In our previous work, a non-equiatomic Ni2Co1Fe1V0.5Mo0.2 MEA was designed by adding V and Mo elements with bigger atomic size to heighten solution strengthening effect. Due to larger atomic size mismatch and more severe lattice distortion, the Ni2Co1Fe1V0.5Mo0.2 MEA exhibits stronger strain hardening effect than that in CoCrFeMnNi HEA. In present work, the low-cycle fatigue behavior of the non-equiatomic Ni2Co1Fe1V0.5Mo0.2 MEA with heterogeneous grain structures was further investigated. The heterogeneous Ni2Co1Fe1V0.5Mo0.2 MEA exhibits high fatigue resistance at 0.25 % strain amplitude (51285 N), attributed to the pronounced dislocation planar slip and formation of stacking faults. At 0.3 % and 0.5 % strain amplitudes, dislocation interactions (including tangles and microbands) induced by extensive dislocation cross-slip result in obvious cyclic hardening but reduced lifetime. The findings assess the effect of solid solution strengthening on the fatigue behavior of MEAs. The fatigue cracks form either along slip bands in large grains or grain boundaries of small grains.