Spinal cord injury (SCI) is one of the most devastating neural injuries without effective therapeutic solutions. Astrocytes are the predominant component of the scar. Understanding the complex contributions of reactive astrocytes to SCI pathophysiologies is fundamentally important for developing therapeutic strategies. We have studied the molecular changes in the injury environment and the astrocyte-specific responses by astrocyte purification from injured spinal cords from acute to chronic stages. In addition to protein-coding genes, we have systematically analyzed the expression profiles of long non-coding RNAs (lncRNAs) (>200 bp), which are regulatory RNAs that play important roles in the CNS. We have identified a highly conserved lncRNA, Zeb2os, and demonstrated using functional assays that it plays an important role in reactive astrogliosis through the Zeb2os/Zeb2/Stat3 axis. These studies provide valuable insights into the molecular basis of reactive astrogliosis and fill the knowledge gap regarding the function(s) of lncRNAs in astrogliosis and SCI. Display omitted •Transcriptomes reveal expression dynamics of both coding and long non-coding RNAs•Zeb2os and Zeb2 are upregulated in astrocytes in acute and chronic stages and co-localize•Knockdown of Zeb2os leads to reduced astrogliosis, lesion size, and Zeb2 and Stat3 expression Wei et al. comprehensively investigate the coding and long non-coding gene expression changes and astrocyte-specific responses in injured spinal cord tissue and purified astrocytes from acute to chronic stages. Bioinformatic and functional analysis identify a conserved lncRNA Zeb2os that plays an essential role in reactive astrogliosis through the Zeb2os/Zeb2/Stat3 axis.