Objective To explore the occurrence and influencing factors of surgical site infection (SSI) following craniotomy, put forward intervention measures and establish a risk prediction model. Methods Patients undergoing craniotomy in a tertiary first-class hospital in 2020 were surveyed retrospectively, influencing factors for SSI follo-wing craniotomy were analyzed, risk prediction model was established, and the model was verified with the data in the first half of 2021. Results Incidence of SSI among 203 cases of craniotomy was 17.73%, multivariate logistic regression analysis showed that 5 factors were independent factors influencing SSI following craniotomy: peri-operative use of H₂ receptor blockers and glucocorticoids, rational use of antimicrobial agents, diabetes mellitus, and operation time ≥180 minutes. The SSI risk prediction model (AUC=0.818) was established, and the cut-off point value of the score was 3.5, incidence of SSI was high when score ≥3.5, the verified accuracy rate was 85.19%, and the verification effect was good(χ²=24.279, P < 0.001). Conclusion Patients undergoing craniotomy have a higher incidence of SSI, peri-operative use of antimicrobial agents and protective use of H₂ receptor blockers can reduce SSI; long operation time, diabetes mellitus and peri-operative use of glucocorticoids are independent risk factors for SSI. The risk prediction model of SSI in craniotomy based on its independent influencing factors has high prediction accuracy.