Gauge-Higgs grand unification theories are models of gauge-Higgs unification that extend the electroweak group into a simple group that includes the color symmetry. The minimal option is a gauge-Higgs grand unification based on the SU(6) gauge group, mirroring SU(5) grand unification in 4D while providing a solution to the hierarchy problem. We explore different minimal and realistic novel incarnations of SU(6) gauge-Higgs grand unification. We submit the setup to the various flavor hierarchies observed in nature and, utilizing the power of the fifth dimension, identify an embedding that provides a compelling model of quarks and leptons that naturally explains the mass hierarchies and the CKM/PMNS structure. We perform a detailed study of quark- and lepton-flavor constraints (which are intimately related due to the GUT nature) together with an analysis of the Higgs potential which arises at the loop level. Electroweak precision constraints on the model are discussed and the rich scalar sector is analyzed. Future flavor constraints from upcoming experiments will provide a stringent test for this class of models, while a scalar singlet and leptoquark provide unique targets for current and future collider experiments to probe this solution to various open questions in nature.