Background: Carbapenem-resistant enterobacteriaceae (CRE) is associated with high mortality in critically ill patients, with limited treatment options. This study aims to compare clinical response, microbiological response, and mortality in patients treated with ceftazidime–avibactam with or without aztreonam (CAZ–AVI + AZT) and colistin or polymyxin B (polymyxins) in CRE infections. Materials and methods: This single-center prospective observational study included adult patients with CRE infections treated with CAZ–AVI+AZT or polymyxins between January 2022 and December 2022 at a Tertiary Care Medical Center in India. The clinical response, microbiological response, and mortality were compared between the two groups using a Cox multivariate regression model adjusted for the baseline SOFA score and comorbidities. Results: A total of 89 patients were enrolled, with 59 (66%) patients receiving CAZ–AVI + AZT and 30 receiving polymyxins. Baseline demographics and clinical characteristics were similar between the two groups. The Cox multivariate regression analysis showed a statistically significant difference in clinical failure on day 14 with the CAZ–AVI + AZT group vs polymyxins (HR = 0.78, 95% CI 0.63–0.95, p = 0.018). There was no difference in microbiological failure (HR = 1.08, 95% CI 0.66–1.77, p = 0.76), microbiological relapse (HR = 0.75, 95% CI 0.36–3.02, p = 0.62), and hospital mortality (HR = 1.04, 95% CI 0.75–1.43, p = 0.796) between the two groups. Conclusion: Treatment with ceftazidime–avibactam with or without aztreonam for CRE infections associated with a better clinical response compared with polymyxins monotherapy but without any difference in microbiological response or mortality.