This study aimed to investigate the characteristics of uncertainty in illness and the coping styles of patients with severe coronavirus 2019 (COVID-19) and to explore their relationship to provide effective guidance for clinical nursing. A cross-sectional survey was used to investigate 56 severe patients with COVID-19 in a designated hospital in Wuhan. A general information questionnaire, the Mishel Uncertainty in Illness Scale for Adults (MUIS-A) and the Medical Coping Modes Questionnaire (MCMQ) were used to collect the data. A statistical analysis was performed. The total score of the MUIS-A was a 66.29 ± 17.25 which was at a low level, while the total score of the MCMQ was 54.16 ± 6.39. The scores of facing and avoiding were significantly higher than those in the norm. The difference in the yielding dimension of patients with different family economic situations was statistically significant. The total score of MUIS-A correlated negatively with the coping style of facing and avoiding and positively correlated with the coping style of yielding. The coping style of patients was one of the factors influencing uncertainty in illness. Nursing staff need to pay close attention to the psychological state of their patients, understand their coping styles and actively correct negative coping styles to reduce the uncertainty in illness and promote physical as well as mental recovery.