This study explores the impact of employee resilience and organizational culture on sustainable performance within tertiary hospitals in Oyo State, Nigeria. Using a mixed-methods research design, data were collected from 338 healthcare professionals across four major hospitals through structured questionnaires and in-depth interviews. The study aimed to examine both the direct influence of employee resilience on performance outcomes and the moderating role of organizational culture in this relationship. Quantitative data were analyzed using multiple regression techniques. Findings reveal that employee resilience significantly predicts sustainable performance (β = 0.514, p < 0.001), emphasizing the importance of cognitive, behavioural, and contextual adaptability in improving healthcare delivery. Organizational culture also demonstrated a significant positive impact on performance (β = 0.403, p < 0.001), with attributes such as openness, collaboration, and innovation contributing to enhanced operational outcomes. Furthermore, the interaction between resilience and culture (β = 0.247, p = 0.003) confirmed that a supportive culture strengthens the resilience-performance link. The study is underpinned by the Resource-Based Theory, Conservation of Resources Theory, and Social Exchange Theory, all of which reinforce the strategic importance of human capital and organizational environment in sustaining institutional excellence. The research recommends integrating resilience-building into staff development programmes and fostering a culture of trust, communication, and support across healthcare institutions. The findings have practical implications for hospital administrators, policymakers, and human resource managers seeking to improve healthcare quality, employee well-being, and institutional sustainability in Nigeria’s healthcare system.