Objective Explore measures to avoid spilling the vaccine solution during the injection of the COVID-19 vaccine. Methods From January 29, 2021 to January 30, 2021, 990 vaccinators were selected as the experimental group by convenient sampling method, and the in-bottle exhaust method was used; 577 vaccinators were selected as the control group, and the conventional exhaust method was used. Observe the incidence of vaccine spillage in the two groups during exhaust. Results The incidence of external spilling in the experimental group was 0%, and that in the control group was 7.28%. The incidence of external spilling in the experimental group was lower than that in the control group, and the data difference between groups was statistically significant (P<0.05). Conclusion Implementing the in-bottle exhaust method in the vaccine injection can effectively reduce the incidence of liquid spills, reduce nucleic acid pollution, and ensure that the vaccine is injected at the prescribed dose. At the same time, the operation is simple and easy, which improves the nurse""s vaccination efficiency, and has a higher promotion and application value.