Background: The quality of well-being of the older population is a crucial determinant of successful aging as well as the achievement of the United Nations Sustainable Development Goals (SDG target 3). However, the impact of psychosocial-spiritual factors on well-being is affected by the level of general health conditions in the older population. Previous studies have focused more on the physical health and psychological well-being nexus, but the role of general health conditions in mediating the association between psychosocial-spiritual factors and well-being in the older population in Africa was not investigated. This study, therefore, examined the psychosocial-spiritual factors associated with well-being in the older population in Africa with a focus to determine the contribution of all the psychosocial-spiritual factors when mediated by general health conditions. Methods: In this regard, a quantitative research methodology was adopted using a descriptive survey. A total of 833 elderly people with a mean age of f 68.04±6.71 years were recruited, comprising 484 females and 399 males in five municipalities. Results: The findings revealed that general health conditions, quality of life, social support, and social network are significantly associated with well-being in older people. Furthermore, the mediating effect of general health conditions had an inverse association with well-being. Conclusion: Accordingly, a commitment to quality of life, healthcare services, social support, and family social network is effective for Africa to achieve healthy lives and promote well-being for individuals of all ages.