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Workplace stress and nurse retention are critical challenges in healthcare, affecting organizational stability and public health outcomes. Therefore, this study investigates the impact of stressors and job satisfaction on nurses’ turnover intentions in the western region of Ghana, with a focus on the moderating role of transformational leadership. Methodologically, a descriptive cross-sectional design was employed to collect data from 364 registered nurses working in four hospitals. Participants completed an online questionnaire measuring stress factors, job satisfaction, turnover intentions, and transformational leadership. Structural equation modelling was employed to analyze the data using Mplus 8.3. The results revealed stressors (stress from workload, superiors, and coworkers and daily life) significantly increased nurses’ turnover intentions while negatively influencing job satisfaction. Job satisfaction was inversely associated with turnover intentions, and transformational leadership moderated this relationship, reducing the likelihood of such intentions. The findings highlight the importance of fostering job satisfaction and implementing transformational leadership strategies, such as mentorship and effective stress management, to alleviate workplace stress and enhance nurse retention. These insights offer valuable guidance for hospital administrators and policymakers in designing interventions to improve nurse retention and overall organizational performance.