Introduction: Cardiac implantable electronic devices (CIEDs) induce a foreign body reaction and persistent inflammatory response that produces a fibrotic capsule around the implanted material. The study’s aim was to investigate the ability of small intestinal submucosa (SIS) extracellular matrix (ECM) envelopes to mitigate fibrotic tissue formation and secure devices within healthy, vascularized tissue. Methods: Clinically relevant pacemakers without leads were subcutaneously implanted in a pre-clinical rabbit model. Eleven CIEDs were placed in CanGaroo ECM Envelopes, while ten devices were implanted without envelopes and analyzed at 13 and 26 weeks. The subcutaneous pocket and newly formed connective tissue adjacent to the CIED were evaluated by an independent, blinded pathologist for the local tissue response and constructive remodeling. CIED movement in the pocket was also documented as implant sites were prone to abrasion due to normal rabbit behavior. Results: CanGaroo Envelopes surrounding the CIEDs remodeled into native tissue with normally organized collagen. The tissue had a lower average thickness at 13 and 26 weeks compared to tissue encapsulating CIEDs without envelopes. The tissue also scored significantly higher in neovascularization versus capsule tissue surrounding CIEDs without envelopes at 26 weeks. Use of the ECM envelope reduced the incidence of device flipping within the pocket by 40% compared to CIEDs without envelopes, showing the ability of CanGaroo Envelopes to secure CIEDs in place. Conclusions: CanGaroo ECM Envelopes remodeled into native, vascularized tissue surrounding clinically applicable CIEDs. This thinner, healthy tissue pocket secured CIEDs and significantly improved stabilization versus devices without envelopes over 26 weeks.