To investigate the relationship between endoplasmic reticulum (ER) stress mediated by old astrocyte specifically induced substance (OASIS) and astrogliosis in spinal cord injury (SCI). SCI models were established using adult male mice deficient for OASIS and C57BL/6 (wild-type mice) mice. After SCI, recovery and astrogliosis were examined in the mice at specific time points using functional and histological methods. After SCI, functional recovery was better in the OASIS-deficient mice than in the wild-type mice. OASIS deletion did not inhibit astrocyte migration but reduced the excessive accumulation of N-cadherin-expressing reactive astrocytes that formed the glial scar around the injury site. In addition, OASIS deletion increased the number of serotonin-positive axons in spinal cord regions caudal to the injury site. These findings suggested that the OASIS-mediated ER stress response inhibits the repair of the injured spinal cord by promoting the development of N-cadherin-expressing reactive astrocytes that form glial scars following injury. OASIS deletion inhibited the development of N-cadherin-positive reactive astrocytes that form glial scars and promoted axon growth and functional recovery after SCI. These results suggest that the ER stress response mediated by OASIS could be a new target in the treatment of SCI.