Objective To explore the changes of hypoxia inducible factor-1α （HIF-1α） and miRNA-21 levels in brain contusion patients within 24 hours after injury and their correlation with prognosis. Methods Thirty patients with brain contusion in the Neurosurgery Department of Qinghai Provincial People's Hospital from March 2021 to November 2022 were in the brain contusion group， while 15 healthy individuals who underwent physical examination in Physical Examination Center were included in the control group during the same period. Two groups of serum HIF-1α and miRNA-21 levels were detected using enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction， respectively. The severity of the patient's trauma was evaluated using the Glasgow Coma Scale （GCS）， and the patient was divided into a decreased GCS score group （n=14） and an increased GCS score group （n=16） based on changes in the GCS score 7 days after admission. The Glasgow Outcome Scale （GOS） score of 1 to 3 points 30 days after injury was defined as poor prognosis. Spearman correlation was used to analyze the relationship between GCS score and HIF-1α and miRNA-21 in patients with brain contusion， and the influencing factors of poor prognosis were analyzed through multivariate Logistic regression. Receiver operating characteristic （ROC） curve was used to evaluate the diagnostic value of miRNA-21 and HIF-1α for poor prognosis in patients with brain contusion. Results The serum levels of HIF-1α and miRNA-21 in the brain contusion group were higher than those in the control group， with statistical differences （t=-5.991， -6.722； P＜ 0.05）. The serum levels of HIF-1α and miRNA-21 were negatively correlated with GCS score and GOS score （r=-0.74， -0.54， -0.51， -0.62； P＜ 0.001）， while the serum levels of HIF-1α and miRNA-21 were positively correlated （r=0.50， P＜ 0.001）， and the differences were all statistically significant. On the seventh day after admission， the HIF-1α level in the increased GCS score group was lower than that in the decreased GCS score group， and the difference was statistically significant （P ＜ 0.05）. There was no statistically significant difference in miRNA-21 levels between the two groups （P ＞ 0.05）. The specificity and sensitivity of serum HIF-1α levels of 305.00 pg/ml and miRNA-21 levels of 3.95 for distinguishing patients with poor prognosis were 90.5% and 66.7%， 95.2% and 66.7%， respectively. Conclusions Serum HIF-1α and miRNA-21 may be useful biomarkers for predicting the prognosis of brain contusion.