Cell apoptosis or necrosis, extracellular matrix loss, and excessive inflammation may induce tendon graft degeneration. The impairment in the regeneration capability of nerve fibers and blood vessels may be the critical cause. Calcitonin gene-related peptide (CGRP), exhibiting a short half-life, favors cell proliferation, nerve fiber regeneration and angiogenesis. We aimed to investigate the effects of CGRP receptor-mediated signaling on tendon graft integrity and study if the modulation pathways are ascribed to cell proliferation, nerve fiber and blood vessel regeneration. A total of three groups in mice with ACL reconstruction were established:​ the control group (PBS treatment), the adenovirus vectors expressing CGRP receptor (CALCRL) treated group (Adv-Calcrl treatment), and the adenovirus vectors carrying shRNA targeting Calcrl treated group (Adv-shCalcrl treatment). The histological assessment indicated the Adv-Calcrl treatment was favored while the Adv-shCalcrl significantly impaired tendon graft integrity. TUNEL staining revealed a significant decreased number of apoptotic cells in the Adv-Calcrl group relative to the control group and the adv-shCalcrl group. Compared to the control group and the Adv-shCalcrl group, the Adv-Calcrl group showed significantly enhanced proliferation of nestin positive cells. Of note, the Adv-Calcrl treatment significantly increased EMCN expression at the tendon graft relative to the control and the Adv-shCalcrl groups, which may be ascribed to attenuation of the Hippo signaling pathway. Importantly, the Adv-Calcrl treatment significantly increased sensory nerve fibers and also PIEZO2 levels. Our results demonstrate the activation of CGRP receptor-mediated signaling attenuated tendon graft degeneration, which was ascribed to enhanced proliferation of Nestin positive cells, angiogenesis, and nerve fiber outgrowth.