BACKGROUND: COVID-19 and the associated measures to mitigate the spread of the virus have significantly disrupted nursing education. PURPOSE: The purpose of this study was to examine the relationship between quality of life (QoL), resilience, and associated factors among nursing students during the unprecedented COVID-19 pandemic and subsequent social distancing requirements. METHODS: A cross-sectional study using an anonymous survey with nursing students (n = 152) was conducted at a public university in rural Appalachia in April 2020. Instruments included World Health Organization Quality of Life-BREF, Connor Davidson Resilience Scale, demographics and school-related questionnaires, and an open-ended question. Data were analyzed using descriptive, bivariate, and multiple linear regression analyses. RESULTS: Resilience, having online experience, and being well prepared for online learning were associated with each QoL domain. Remarkably, 21% to 54% of nursing student QoL scores indicated poor QoL. CONCLUSIONS: Cultivating resilience among nursing students may improve QoL, help with academic success, and prepare students to sustain the demands associated with the nursing profession.