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The experiments and molecular dynamics simulations were performed to obtain the orientation effect on the behavior and mechanism of irradiation resistance in the RAFM steel. The irradiation surface morphologies, Frenkel defects, and clusters analysis reveal that the irradiation resistance of different orientations is as follows, (110) > (100) > (112) > (233) > (111) orientation. Additionally, the (233) orientation is easier to form vacancy defect clusters, while the (111) orientation is easy to form a large number of small clusters, which are determined by the clustering rates of interstitial atomic and vacancy clusters. Surface energy, atomic arrangement density, and atomic bonds play a significant role in the orientation effect on the radiation damage resistance. The radiation damage resistance of different orientations increased with the increase of atomic arrangement density and atomic bonding strength, while it decreased with the increase of surface energy. [Display omitted] • Both experiments and simulations are applied to reveal orientation effects on radiation damage. • The resistance of irradiation damage of orientations is (110) > (100) > (112) > (233) > (111). • The size, types, and number of clusters are determined by the clustering rates of Frenkel defects. • The orientations mechanism is determined by their surface energy and atomic bonding strength. [ABSTRACT FROM AUTHOR]