Objective To evaluate the efficacy of hemostatic powder on preventing delayed bleeding after endoscopic submucosal dissection (ESD). Methods Patients who received ESD in the First Affiliated Hospital of Soochow University and Yulin No.2 Hospital from June 2017 to August 2018 were enrolled with informed consents, and randomly divided into the study group and the control group. Hemostatic powder was applied on post-ESD ulcer after routine hemostasis method in the study group, and the control group was given routine hemostasis method only. The time and dosage of hemostatic powder spraying and its adverse events were observed in the study group. The operation time, rate of delayed bleeding (within 30 days after operation) and early delayed bleeding (within 48 hours after operation), and postoperative hospital stay were compared between the two groups. Results A total of 196 patients were enrolled including 97 in the study group and 99 in the control group. The baseline data were comparable between the two groups (all P>0.05). In the study group, the time to spray powder was 68.78±19.75 s, dosage was 2.51±0.93 g. Powder delivery catheter was blocked in one case (1.03%,1/97). No adverse event was reported during 30 days of follow-up. The operation time was not statistically different in the study group and the control group (61.92±11.71 min VS 59.76±11.01 min, t=1.330, P=0.185). The delayed bleeding rate of the study group was significantly lower than that of the control group [1.03% (1/97) VS 8.08% (8/99), P=0.035]. There was no case of early delayed bleeding occurred in the study group, while 6 cases (6.06%, 6/99) in the control group (P=0.029). The postoperative hospital stay was not statistically different between the study group and the control group (4.57±0.85 d VS 4.86±1.37 d, t=1.778, P=0.077). Conclusion Although capacity of hemostatic system remains to be improved, hemostatic powder is an effective, safe and simple method to reduce delayed bleeding rate after ESD, especially on early delayed bleeding.