Nurse well-being is critical for safe and efficient health care delivery, particularly in complex and demanding specialties like nephrology. However, levels of burnout are rising and may relate to a largely unexplored phenomenon: loneliness. This study investigated the phenomenon of nurse loneliness as a potential factor in burnout. A mixed-methods approach was used to investigate burnout and loneliness in a national sample of nephrology nurses. Together with workforce demographics, burnout and loneliness were measured, prevalence was estimated, and correlations were examined. Interpretive descriptive inquiry and analysis was used to develop a richer understanding of nurse loneliness in the context of burnout. In the study population (n = 217), rates of burnout were low, but positively correlated with loneliness. Qualitative interviews reveal that organizational and systemic pressures, recognition and peer support, work environment and demands, and physical and emotional well-being are components of the experience of current nephrology nurses related to loneliness and burnout.