Reduced Activation Ferritic/Martensitic (RAFM) steel is a candidate blanket material for a fusion reactor, which should have outstanding performance under extreme environments containing complex thermal and stress damage during operation. To date, the properties under a single-axial loading type of tensile, creep and fatigue have been extensively reported, while the multi-axial loadings were rarely studied. Here, the multi-axial fatigue behaviors of a RAFM steel were investigated in an axial-torsional cyclic tester with controlled strain and different loading paths. The results show that the fatigue behavior of the RAFM is strongly determined by the shear-stress condition, where the lifetime under the pure torsional loading is only 16% of the uniaxial cyclic loading one. The fatigue life of the specimens under multi-axial loadings with a phase angle of 0° or 180° are comparable to that of uniaxial tension-compression one. However, it was decreased by ∼28% as the loading angle changed to 90° with a circular path. Besides, we found the fatigue softening under the proportional multi-axial loading while additional hardening in the non-proportionally multi-axial cyclic loading related to the dislocation activities during loadings. Under the proportional-multiaxial loading and uniaxial tension-compression loading and torsion loading, the high density of dislocation was rearranged and annihilated by the cyclic shear stress, while the tempered martensite lath structure was mainly retained. However, under the non-proportional multi-axial loading, dislocations transform the lath structure into a finer cell structure, improving the resistance upon fatigue deformation.