There is a lack of knowledge regarding perceptions, feelings, and experiences of Ghanaian patients living with ESRD. This study aimed to discover the experience and meaning of living with ESRD. This qualitative study was conducted using Heideggerian hermeneutic phenomenology. A total of 13 participants were purposefully selected, and data was collected through individual semi-structured interviews. The recorded interviews were transcribed and analyzed using Diekelmann, Allen, and Tanner method. After the final analysis, five main themes emerged: Spiritual fluctuation, Living in uncertainty, Period of agony and frustration, Tough fortification, and Changed roles and status. This study provided deep insight and understanding regarding the lived experiences of patients living with end-stage renal disease in Ghana. The results of this study may benefit nursing care in terms of considering the patients’ lived experiences to provide quality and person-centered care.