Introduction Early antibacterial treatment is critical for patients with hematologic malignancies (HMs) and sepsis. Droplet digital polymerase chain reaction (ddPCR) can rapidly detect pathogens and antimicrobial resistance (AMR) genes, but its clinical value in HMs is unknown. This study aimed to systematically evaluate the role of ddPCR in diagnosis, clinical outcomes, and antimicrobial stewardship. Methods From January 2023 to March 2025, 400 patients with hematologic malignancies (HMs) and sepsis were enrolled in the study. Of these, 150 received both ddPCR and blood culture (BC), while 250 underwent BC alone. Using propensity score matching (PSM), as well as subgroup and sensitivity analyses, we evaluated ten indicators, including 28-day mortality, treatment efficacy, and antibiotic use density (AUD). Results ddPCR showed a 49.33% positive rate (vs. BC’s 17.50%, P < 0.01) with a 4.06-h diagnostic turnaround (vs. 72.47 h for BC, P < 0.01), achieving 70.37% sensitivity and 55.28% specificity. The ddPCR group had lower 28-day mortality (HR = 0.55, P = 0.01), higher clinical response rates, and greater inflammatory marker decline. Antimicrobial optimization via ddPCR improved efficacy to 85.11%, with reduced AUD (OR = − 28.93, P < 0.01), the quantity and proportion of combined antimicrobial usage. However, a non-significant difference was observed in the proportion of antibacterial treatment costs (P = 0.14). PSM and sensitivity analysis results were consistent, indicating data robustness. Conclusions ddPCR outperforms BC in diagnostic efficiency for patients with HMs and sepsis, accelerating pathogen and AMR genes identification, optimizing antibacterial therapy and management, improving clinical effectiveness, and reducing 28-day all-cause mortality. The findings support the application of ddPCR in immunosuppressed populations. Graphical Abstract