Elemental substitution and doping validate the optimization of chemical and physical properties of functional materials, and the composition ratio of the substituting atoms generally determines their properties by changing their geometric and electronic structures. For atomically precise nanoclusters (NCs) consisting of countable atom aggregates, the composition can be controlled accurately to provide an ideal model to study the heteroatom substitution effects. Since aluminum (Al) and boron (B) both belong to group 13 in the periodic table, the effect of B atom substitution on Aln NCs can be investigated while maintaining the total number of valence electrons in AlnBm NCs. In this study, oxidative reactivities of small Al NCs with B atom substitution are studied for AlnBm NCs (m = 1, n = 6-14 and m = 2, n = 11) supported on organic surfaces by using X-ray photoelectron spectroscopy and oxygen molecule (O2) exposure measurements. Before completing the endohedral B@Al12- superatomic NC, one B atom substitution in Al NCs (AlnB) enhances oxidative reactivities 3-20 times compared to those of Aln+1, particularly for n ≤ 11. When one Al atom of Al12B is further substituted by a B atom to form Al11B2, the reactivity drastically increases (6.6 × 102 times), showing that the B atom substitution makes the NC chemically active or inactive geometrically depending on the exohedral or endohedral site for the B atom in the Al NC. In addition, density functional theory calculations show that the electronegative B atom contributes to forming a locally positive Al site to facilitate O2 adsorption except in Al12B, in which the B atom is geometrically shielded by the surface of the Al12 cage in B@Al12.