We study D-brane inspired models with gauge symmetry in the context of split supersymmetry. We consider configurations with one, two and three Abelian branes and derive all hypercharge embeddings which imply a realistic particle content. Then, we analyze the implications of split supersymmetry on the magnitude of the string scale, the gauge coupling evolution, the third family fermion mass relations and the gaugino masses. We consider gauge coupling relations which may arise in parallel as well as intersecting brane scenarios and classify the various models according to their predictions for the magnitude of the string scale and the low energy implications. In the parallel brane scenario where the branes are superposed to or brane stacks, varying the split-SUSY scale in a wide range, we find three distinct cases of models predicting a high, intermediate and low string scale, , and , respectively. We further find that in the intermediate string scale model the low energy ratio is compatible with Yukawa unification at the string scale. Furthermore, we perform a similar analysis for arbitrary Abelian gauge coupling relations at corresponding to possible intersecting brane models. We find cases which predict a string scale of the order that accommodate a right-handed neutrino mass of the same order so that a seesaw type, light, left-handed neutrino component is obtained in the sub-eV range as required by experimental and cosmological data. Finally, a short discussion is devoted to the gaugino masses and the lifetime of the gluino.