We discuss different SU(5) low-energy realizations and illustrate their use with the diphoton excess and Higgs flavor violation, which require new physics at the TeV scale. In particular, we study two scenarios for a 750 GeV resonance: in the first one the resonance belongs to the adjoint of SU(5), being either an SU(2)L singlet or a triplet, while in the second case the signal is due to the CP-even and CP-odd states of a new SU(2)L Higgs doublet belonging to a 45H or a 70H representations, giving rise to a two-Higgs doublet model at low energies. We study the fine-tuning needed for the desired members of the multiplets to be light enough, while having the rest at the GUT scale. In these scenarios, the production and decay into photons of the new resonance are mediated by the leptoquarks (LQ) present in these large SU(5) representations. We analyze the phenomenology of such scenarios, focusing on the most relevant predictions that can help to disentangle the different models, like decays into gauge bosons, Standard Model (SM) fermions and LQs pair production. In the case of the 45H (the Georgi–Jarlskog model), we also study the possibility to have Higgs flavor violation. We find that Bs mixing limits (in addition to τ→μγ) always imply that Br(h→τμ,bs)≲10−5.