Febrile neutropenia (FN) is a serious complication in patients with hematologic malignancies following treatments such as chemotherapy and hematopoietic stem cell transplantation. It is typically managed with broad-spectrum antibiotics (BSA), but the optimal duration of BSA therapy remains controversial. This meta-analysis aimed to assess the clinical efficacy and safety of early antibiotic de-escalation in patients with hematologic malignancies with FN before hematopoietic recovery, compared to those who continued BSA until hematopoietic recovery. Statistical analysis included pooled odds ratios (OR) for mortality and secondary adverse outcomes, along with subgroup analysis to identify patient populations that may benefit from early de-escalation. Ten studies, mostly retrospective observational designs, were included. Early de-escalation significantly reduced mortality risk (OR 0.20, 95% CI 0.06-0.69). Subgroup analyses showed mortality benefits in older patients (>55 years old, OR 0.42, 95% CI 0.18-0.98) and in higher-quality studies (OR 0.07, 95% CI 0.01-0.62). No significant differences were observed for infection-related ICU admissions, bacteremia, recurrent fever, or Clostridium difficile infection (CDI). In conclusion, early de-escalation of BSA in patients with hematologic malignancies and developing FN after treatment significantly reduces mortality risk without increasing major adverse events. These findings support the use of early de-escalation and highlight the need for personalized strategies to improve patient outcomes.