Objective The prevalence of Carbapenem-Resistant Gram-Negative Bacteria (CR-GNB) is rapidly escalating, presenting a significant global public health concern. This study aims to evaluate the survival rate of early appropriate therapy with polymyxin B (PMB), and adverse drug reactions of PMB in treating severe burn sepsis caused by CR-GNB infections. Methods We retrospectively analyzed 72 patients with severe burn sepsis caused by CR-GNB infections from January 1, 2018, to December 30, 2023. These patients received a treatment regimen based on PMB for at least three days. We collected data on the patient's clinical characteristics, microbiological results, details of PMB treatment, adverse drug reactions with PMB, and mortality. We compared the 30-day mortality rates between patients who received early appropriate therapy (the timely administration of an active antimicrobial agent within 48 h after the onset of infection) and those who underwent non-early appropriate therapy, multivariate Cox regression analysis was employed to evaluate factors impacting the 30-day survival rate of patients, and the adverse drug reactions caused by PMB were also analyzed. Results Among the 72 patients with severe burn sepsis, the clinical effective rate was 69.4% (50/72), the 30-day all-cause mortality rate was 31.9% (23/72) and the 30-day sepsis-associated mortality rate was 27.8% (20/72). The adverse drug reactions of PMB included nephrotoxicity and skin pigmentation, with an incidence of 19.4% (14/72) and 15.3% (11/72), respectively. The patients who received early appropriate therapy had a lower mortality rate, lower SOFA scores and more wound infections compared to those who underwent non-early appropriate therapy (all P < 0.05). The univariate Cox regression analysis showed that age, hypertension, SOFA score at the time of sepsis diagnosis, and early appropriate therapy with PMB were associated with both 30-day all-cause mortality and sepsis-associated mortality in severely burned patients (all P < 0.05). Additionally, In the multivariate Cox regression analysis, early appropriate therapy with PMB was identified as an independent protective factor for both 30-day all-cause mortality (HR = 0.183 [95% CI 0.071-0.468], P < 0.001) and sepsis-associated mortality (HR = 0.150 [95% CI 0.054-0.414], P < 0.001) in severely burned patients. Conclusions Polymyxin B is an effective option for burn sepsis patients in treating CR-GNB infections. Early appropriate therapy with PMB significantly improved the survival rate of severe burn sepsis patients infected with CR-GNB.