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Teneurins are type II transmembrane proteins comprised of four phylogenetically conserved homologs (Ten-1-4) that are highly expressed during neurogenesis. An additional bioactive peptide named teneurin C-terminal-associated peptide (TCAP-1-4) is present at the carboxyl terminal of teneurins. The possible correlation between the Ten/TCAP system and brain injuries has not been explored yet. Thus, this study examined the expression of these proteins in the cerebral cortex after mechanical brain injury. Adult rats were subjected to cerebral cortex injury by needle-insertion lesion and sacrificed at various time points. This was followed by analysis of the lesion area by immunohistochemistry and conventional RT-PCR techniques. Control animals (no brain injury) showed only discrete Ten-2-like immunoreactive pyramidal neurons in the cerebral cortex. In contrast, Ten-2 immunoreactivity was significantly up-regulated in the reactive astrocytes in all brain-injured groups ( p < 0.0001) when compared to the control group. Interestingly, reactive astrocytes also showed intense immunoreactivity to LPHN-1, an endogenous receptor for the Ten-2 splice variant named Lasso. Semi-quantitative analysis of Ten-2 and TCAP-2 expression revealed significant increases of both at 48 h, 3 days and 5 days ( p < 0.0001) after brain injury compared to the remaining groups. Immortalized cerebellar astrocytes were also evaluated for Ten/TCAP expression and intracellular calcium signaling by fluorescence microscopy after TCAP-1 treatment. Immortalized astrocytes expressed additional Ten/TCAP homologs and exhibited significant increases in intracellular calcium concentrations after TCAP-1 treatment. This study is the first to demonstrate that Ten-2/TCAP-2 and LPHN-1 are upregulated in reactive astrocytes after a mechanical brain injury. Immortalized cerebellar astrocytes expressed Ten/TCAP homologs and TCAP-1 treatment stimulated intracellular calcium signaling. These findings disclose a new functional role of the Ten/TCAP system in astrocytes during tissue repair of the CNS.