Objective: To investigate the clinical application of severe early warning nursing mode in children with hand-foot-mouth disease (HFMD). Methods: A total of 60 HFMD children who were admitted to pediatric department of the hospital from April 2017 to February 2019 were enrolled. The random number table method was performed to divide them into an experimental group and a control group, 30 cases in each group. The control group was given routine nursing. The experimental group was given severe early warning nursing mode based on routine nursing. The disappearance time of clinical symptoms, hospitalization time, disease outcome, and satisfaction of their parents were compared between the two groups. The changes in fasting blood glucose (FPG), neuron-specific enolase (NSE) and creatine kinase (CK) levels in both groups before and after intervention were observed. Results: After intervention, levels of FPG, NSE and CK in both groups were decreased (P<0.05). After intervention, contents of FPG, NSE and CK in experimental group were significantly lower than those in control group (P<0.05). Compared with those in control group, fever relieving time, herpes fade time, healing time of oral ulcer, hospitalization time, incidence of critical illness and complications were significantly decreased in experimental group (P<0.05), while nursing satisfaction was increased (P<0.05). Conclusion: Severe early warning nursing mode can significantly reduce incidence of severe HFMD, with relatively good clinical application effect.