Objective To explore the predictive value of serum CXC chemokine ligand 12 (CXCL12) level for poor prognosis of patients with craniocerebral injury. Methods A retrospective analysis was performed on the data of 124 patients with craniocerebral injury and 86 subjects who underwent physical examinations, who were assigned to group A and group B, respectively. The serum CXCL12 level was determined. Results The serum CXCL12 level was significantly higher in group A than in group B, the serum CXCL12 level was significantly higher in patients with severe condition than in those with mild and moderate conditions, and the serum CXCL12 level was significantly higher in patients with moderate condition than in those with mild condition (P<0.05). The incidence of poor prognosis was 20.97% in group A, significantly higher in patients with severe condition than in those with mild and moderate conditions, the serum CXCL12 level was significantly higher in patients with poor prognosis than in those with good prognosis, with consistent results observed in the serum CXCL12 level between patients with poor prognosis (in mild, moderate, and severe conditions) and those with good prognosis(all P<0.05). The serum CXCL12 level had a satisfactory performance in predicting the poor prognosis in group A. Conclusions The serum CXCL12 level can predict the poor prognosis of patients with craniocerebral injury.