Objective To study the effect of the application timing of vasoactive agents on the prognosis of children in the third stage of hand-foot-mouth disease (HFMD). Methods A retrospective analysis was performed on the medical data of children in the third stage of HFMD between April 2012 and September 2016. According to the application time of vasoactive agents (milrinone combined with phentolamine) after admission, the children were divided into an early stage (within 2 hours after admission) group with 32 children, a middle stage (within 2-6 hours after admission) group with 28 children, and a late stage (more than 6 hours after admission) group with 26 children. Venous blood samples were collected before vasoactive agent treatment and after 24 hours of vasoactive agent treatment to measure the levels of creatine kinase-MB (CK-MB), troponin (TnI), and brain natriuretic peptide (BNP). The recovery time of left ventricular ejection fraction (LVEF), respiratory rate, blood pressure, and heart rate were recorded. The response rate to the treatment within 72 hours of treatment was evaluated. Results The early stage group had a significantly higher overall response rate to the treatment than the middle stage and late stage groups (P < 0.0167). After 24 hours of treatment, there were significant differences in heart rate, blood pressure, respiratory rate, and LVEF among the three groups (P < 0.05). The early stage group showed the most significant improvement in these parameters (P < 0.0167). Compared with the middle stage and late stage groups, the early stage group had significantly shorter recovery time of LVEF, respiratory rate, heart rate, and blood pressure (P < 0.0167). After 24 hours of treatment, the early stage group had a significantly lower level of BNP than the middle stage and late stage groups (P < 0.05). Conclusions Vasoactive agents should be given to children with critical HFMD as early as possible to improve cardiovascular function, reduce the risk of disease progression, and improve prognosis.