This study investigated anxiety, depression, and stress and their influencing factors among nurses during the COVID-19 pandemic and after the flood in Henan Province, China. It aimed to provide the theoretical foundation for the management of relevant hospital departments, improvement of nursing quality, implementation of antiepidemic work, and other relevant studies. In December 2019, COVID-19 was reported in Wuhan, China and became a global pandemic. In July 2021, unprecedented flooding occurred in Henan Province, China. Under the dual pressure of COVID-19 and the flood, nurses' mental health problems deteriorated. In August 2021, 1229 nurses from various departments of the First Affiliated Hospital of Xinxiang Medical University in Xinxiang City, Henan Province,Chinawere invited to participate in a questionnaire survey using a general condition questionnaire and the Chinese version of the Depression-Anxiety-Stress Scale. Descriptive statistics were used to analyze the status of nurses' anxiety, depression, and stress. Analysis of variance, t-test, and multiple linear regression models were used to analyze the factors influencing anxiety, depression, and stress among nurses. Of the participants, 36.1%, 10.1%, and 15.5% had moderate to high levels of anxiety, stress, and depression, respectively. Moreover, 42 (3.4%) participants experienced high to severe levels of stress, anxiety, and depression. The scores showed significant differences based on gender, harmonious family relationships, department position, work intensity, sleep quality, physical exercise, participation in leisure activities, health status, involvement in emotion management-related training, and attending self-care-related training (all P<0.05). Gender, work intensity, harmonious family relationships, health condition, sleep quality, and participation in leisure activities influenced stress, anxiety, and depression scores. Department position influenced anxiety and stress scores, and average monthly earnings influenced anxiety scores. All the nurses experienced various levels of stress, anxiety, and depression. Related departments should pay special attention to male nurses and nurses with high work intensity, unharmonious family relationships, poor health, and sleep quality, and who engage in fewer leisure activities. It is recommended that departments allocate human resources and arrange schedules reasonably, encourage nurses to participate in more recreational activities, and implement emotion management and self-care-related training to relieve emotional distress, and ultimately maintain nurses' mental health.