In this study, we report the development of efficient Al2O3-supported Ni and promoted Ni–Me (Me = Mo, V, Nb, Ta, Co) catalysts for the oxidative dehydrogenation of ethane. The effect of nickel loading and the impact of the promoters on the performance of the materials are discussed in the light of a detailed physico-chemical characterization of the catalysts by N2 adsorption, XRD, XPS, TGA-H2, and UV-DRS. Nickel was found to interact strongly with alumina, forming surface nickel aluminate-like species in the submonolayer regime, whereas NiO crystallites formed on top of the nickel/alumina interface for multilayer coverages. XPS revealed a chemical modification of the NiO particles accommodated on the alumina support. In terms of catalytic performance, increasing the Ni loading was beneficial and boosted ethane conversion, which surpassed 40% at 450 °C for the highest nickel loading catalyst, whereas ethene selectivity was retained at high levels for all Ni/Al2O3 catalysts. Promotion with V, Mo, Co, Nb, and Ta significantly modified both structural and catalytic properties in ethane oxidative dehydrogenation. The introduction of niobium was the most beneficial for ethane ODH, increasing the reactivity toward ethane by more than 50% at the expense of a relatively small drop (10%) in ethene selectivity.