Cardiac fibrosis plays a key role in the progression of diabetic cardiomyopathy (DCM). Previous studies demonstrated the cardioprotective effects of natriuretic peptides. However, the effects of natriuretic peptide receptor C (NPRC) on cardiac fibrosis in DCM remains unknown. Here, we observed that myocardial NPRC expression was increased in mice and patients with DCM. NPRC-/- diabetic mice showed alleviated cardiac fibrosis, as well as improved cardiac function and remodeling. NPRC knockdown in both cardiac fibroblasts and cardiomyocytes decreased collagen synthesis and proliferation of cardiac fibroblasts. RNA sequencing identified that NPRC deletion up-regulated the expression of TGF-β-induced factor homeobox 1 (TGIF1), which inhibited the phosphorylation of Smad2/3. Furthermore, TGIF1 up-regulation was mediated by the activation of cAMP/PKA and cGMP/PKG signaling induced by NPRC deletion. These findings suggest that NPRC deletion attenuated cardiac fibrosis and improved cardiac remodeling and function in diabetic mice, providing a promising approach to the treatment of diabetic cardiac fibrosis.