Intravascular devices and methods for intramural delivery of dissection fluids and infusates are disclosed herein. In some embodiments, the systems include an infusion assembly that can access a vessel wall at a depth within a layer of the vessel wall and advance a tissue manipulation component at approximately the same depth within the vessel wall to create an intramural space within the vessel layer. The infusion assembly can further deliver an infusate that includes a therapeutic drug or other agent into the intramural space.