The Red Sea represents an incipient ocean basin that is in transition from continental rifting to ocean initiation. In this paper we assess how pre-existing mantle and crustal heterogeneities within the African and Arabian lithospheres influenced rift development and propagation using three-dimensional (3D) brittle-ductile analogue laboratory experiments with a rotational boundary condition. Here we investigate the effect of three different configurations: (i) pre-existing rheological heterogeneities in the crust, (ii) in the lithospheric mantle, and (iii) in both. The experimental outcomes show that a linear weak zone in the lithospheric mantle layer exerts a first-order control on the overall mechanical behaviour of extending lithosphere, rift architecture and style of rifting. Crustal heterogeneities control second-order features, such as the trends of the main boundary escarpments along the rift axis. Our experiments reproduce the geological history of the Red Sea and provide key insights on its deformation history in space and time. We provide, for the first time, 3D dynamic constraints on how pre-existing weak zones in the lithosphere have controlled the temporal evolution of the Red Sea and determined its distinctive present-day morphology. The results find that certain morphological elements of the Red Sea can only be explained by the combined effects of crustal and mantle lithosphere heterogeneities. When applied to other natural examples, our findings provide significant new insights on the role of crustal and lithospheric heterogeneities during continental rifting.