Transonic shock formation and its coupling to local flow separation and streamwise vortices are considered in three-dimensional internal flow over the first turn of a serpentine diffuser. The present investigations indicate that the shock strength is highest at the diffuser’s spanwise corners, where it locks flow separation to its root, with separation decoupling and gradually being displaced downstream toward the midspan, as the shock progressively weakens spanwise. In addition, two counter-rotating vortices that originate at each corner of the D-shaped diffuser inlet strengthen and become displaced along the flow separation domain envelope as a result of interaction of the corner flow with the shock. Fluidic-based flow control is utilized to directly target flow separation, through which it indirectly controls both the dominant streamwise vortices and shock due to inherent internal flow coupling through the pressure field. It is shown that the flow control expands the central domain of the attached flow toward the edges, thereby confining the shock extent to the corners, while decoupling the joint action of the corner vortices as the vortex pair. In addition, some flow control realizations split the shock footprint into the two consecutive legs, arguably altering the normal shock topology into the lambda shape. Along with changing the shock footprint topology, flow control displaces the streamwise vortex pair farther apart and thereby diminishes the cooperative advection of a low-momentum fluid from the wall region into the core flow, thereby effectively coupling to the long-range alteration of the bulk flow. This global effect on the internal flow was quantified by the overall reduction in the total pressure circumferential nonuniformity by about 30%, associated with 1% reduction in total pressure losses.Graphic Abstract: