Background: Subcutaneous pocket infection is a common morbidity associated with the integration of cardiac implantable electronic devices (CIEDs). A new antibiotic-eluting CIED bioenvelope has been developed as a prophylactic measure to mitigate infection and skin erosion caused by device migration. This study investigated the envelope’s regulatory properties in scar formation and vascularization. Methods: Fibroblasts were seeded on either plastic (n = 6) or small intestine submucosal extracellular matrix (SIS-ECM) (n = 6) for 24 h. The culture media were analyzed for proangiogenic and proinflammatory proteins with multiplex. Sham (n = 8) or SIS-ECM (n = 8) was randomly implanted into the dorsal subcutaneous pocket of mice. The implants were excised on day 7, cultured for 24 h, and the media analyzed. Rabbit models were implanted with either synthetic polymer HDPE (n = 12) or SIS-ECM (n = 11). The treatments were excised at weeks 2, 10, and 26 and then stained for analysis. Results: SIS-ECM significantly increased the fibroblasts’ paracrine release of proangiogenic and proinflammatory factors like VEGF-A (p < 0.05) and IL-6 (p < 0.05) compared with plastic. The murine tissue interacting with SIS-ECM released significantly more angiogenic proteins like VEGF-A (p < 0.05) than the sham. The histology analysis of rabbit subcutaneous tissue revealed a decreasing level of inflammation and fibrosis over time with SIS-ECM. Conclusions: The CIED bioenvelope elicited proangiogenic paracrine signaling and reduced fibrotic response in fibroblasts and animal models. Clinical translation of the CIED bioenvelope as an adjunct to regular prophylactic practice may be warranted in the future.