Objective <p>This study aims to compare the efficacy of Ceftazidime/Avibactam (CAZ/AVI) and Colistin Methanesulfonate (CMS) in the treatment of pulmonary infection caused by Gram-negative bacilli after craniocerebral surgery, and analysis of risk factors influencing clinical outcomes.</p> Methods <p>We retrospectively enrolled patients who developed pulmonary infections caused by Gram-negative bacilli following craniocerebral surgery spanning from January 1st, 2023 to June 9th, 2025. These patients were divided into the CAZ/AVI group and the CMS group based on their medication choices. In-hospital mortality and clinical success rate were compared between the two groups. Additionally, logistic regression analysis was performed to assess the association between CAZ/AVI-based treatment regimens and clinical success rate.</p> Results <p>The In-hospital mortality rates of the two groups were 8.51% and 14.63% respectively, both relatively low, and there was no statistical significance (<i>P</i> = 0.367). The clinical success was noted to be significantly higher in CAZ/AVI-based treatment regimens (<i>P</i> = 0.041). In the logistic regression analysis, the clinical success rate was independently associated with the use of CAZ/AVI and the combination of antibiotics. The odds of clinical success rate were 3.062 times higher in patients receiving CAZ/AVI compared to those without CAZ/AVI therapy (95% CI: 1.219–10.646); similarly, the odds ratios (OR) associated with combined antibiotic use was 3.608 (95% CI: 1.235–10.546).</p> Conclusions <p>CAZ-AVI is more effective than CMS in treating pulmonary infections caused by Gram-negative bacilli after craniocerebral surgery. And when combined with other antibiotics, it can significantly enhance the clinical success rate.</p>