Embodiments of the present invention relate to multiple needle catheter-based injection systems to deliver a plug of a therapeutic or other agent. A medical device may include a catheter with a distal end, a proximal end and a catheter lumen extending therebetween and an outer needle disposed in the catheter lumen with a distal end and a proximal end and an outer needle lumen extending therebetween. The medical device may include an inner needle with a distal end and a proximal end, the inner needle being disposed in the outer needle lumen and the distal end of the inner needle to receive and hold a therapeutic plug, and a needle control mechanism coupled to the proximal ends of the outer needle and the inner needle, the needle control mechanism to independently and jointly control ejection and retraction of the outer and inner needles to deliver the therapeutic plug into a target tissue site.