The coronavirus disease 2019 (COVID-19) pandemic continues to pose an unprecedented threat and challenge to public health around the world. Lacking sufficient human resources, nurses are required to undertake an increased workload at the clinical frontline of this epidemic. Additionally, nurses are at a high risk due to their working within close proximity to COVID-19 patients. As a result, they experience increased job stress. To explore the current situation and influencing factors of job stress among clinical first-line nurses fighting COVID-19. A convenience sampling method was used to conduct a questionnaire survey with 110 nurses who were on the clinical frontline of the COVID-19 epidemic in a hospital in Wuhan. The job stress scores of clinical nurses on the frontline of the COVID-19 epidemic were collected (91.42 ± 26.09); the dimensions of work environment and resources as well as workload and time pressure were ranked first and second, respectively. The results of a multiple stepwise regression analysis showed that working hours per day, service years, number of night shifts per week, and level of academic qualification were the main factors affecting the job stress levels of nursing staff. The job stress of nurses on the clinical frontline of the COVID-19 epidemic was found to be at a medium level. Nursing leaders and hospital managers should pay attention to the impact of job stress on frontline nurses, while taking positive and effective measures aimed at eliminating the source of nursing work pressures to stabilize their nursing teams and promote their work in the fight against this epidemic.