To investigate the expressions of plasma cystatin C (Cys-C), D-dimer (D-D) and hypersensitive C-reactive protein (hs-CRP) in patients with intracranial progressive hemorrhagic injury (IPHI) after craniocerebral injury, and their clinical significance. Forty-two IPHI patients and 20 healthy participants (control) were enrolled. The severity and outcome of IPHI were determined according to the Glasgow Coma Scale and Glasgow Outcome Scale, and the plasma Cys-C, hs-CRP and D-D levels were measured. The plasma Cys-C, D-D and hs-CRP levels in the IPHI group were significantly higher than those in the control group (p < 0.01). There were significant differences of plasma Cys-C, D-D and hs-CRP levels among different IPHI patients according to the Glasgow Coma Scale and according to the Glasgow Outcome Scale (all p < 0.05). In the IPHI patients, the plasma Cys-C, D-D and hs-CRP levels were positively correlated with each other (p < 0.001). The increase of plasma Cys-C, D-D and hs-CRP levels may be involved in IPHI after craniocerebral injury. The early detection of these indexes may help to understand the severity and outcome of IPHI.