Natriuretic peptide receptor‐C (NPR‐C) activation by C‐ANP4‐23, a specific agonist for this receptor, has been shown to inhibit key events of the angiogenic cascade (migration, proliferation, and vascular endothelial growth factor—VEGF—production). We investigated whether C‐ANP4‐23 could also inhibit angiogenesis in the sponge model in vivo. In this study, we evaluated the effects of this peptide on inflammatory and angiogenic components of the fibrovascular tissue induced by polyether polyurethane sponge implants in mice. The hemoglobin content (μg/mg wet tissue) and blood flow measurements (laser Doppler perfusion imaging) of the implants, used as an index of vascularization, showed that single or multiple doses of C‐ANP4‐23 reduced angiogenesis in the implants relative to the PBS‐treated group. The peptide exerted an inhibitory effect on nitric oxide production (nitrite levels) and a dual effect on VEGF levels, depending on the number of doses. Histological analysis corroborated the biochemical and functional parameters indicative of neovascularization inhibition (decreased vessel number). The peptide failed to modulate inflammation in our system. The inhibitory effect of C‐ANP4‐23 on the angiogenic component of the fibrovascular tissue induced by the synthetic matrix extends the range of the peptide's actions and may indicate its therapeutic potential in controlling angiogenesis in fibroproliferative diseases. This article is protected by copyright. All rights reserved.