A multi-guidewire sheath (MGS) is provided for cases where simultaneous guidewire access to multiple target arteries is required. Embodiments of the MGS have multiple guidewires in a single sheath configured with a single lumen. The MGS incorporates an engagement system to independently secure the one or more guidewires within the sheath to maintain the separate positions of the guidewires. Embodiments of the MGS are configured with a taper from the desired intra-arterial portion (e.g., conventional French sizes) to a larger diameter for the portion of the sheath outside (distal) the vessel. The distal segment of the MGS has a larger diameter to accommodate the engagement system to secure the independent positions of multiple guidewires, and a hemostatic valve seal and slit mounted in a rotating hub. The engagement system has a series of wire-lock engagement points positioned along the circumference of the MGS.