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Introduction The population of the aged is increasing globally and in Ghana. In 2020, the population aged over 60 years in Ghana was 2,051,903 and this is expected to reach 2.5 million by 2025 and 6.3 million by 2050. Despite the envisaged increase in the number and life expectancy of the older population in Ghana that will require nursing care, there is a paucity of data on nursing staff knowledge and attitudes toward elderly patients in Ghana. Objectives This study, therefore, assessed factors affecting the care of elderly patients among nursing staff in a tertiary referral health facility in the Volta region of Ghana. Methods The study employed a descriptive cross-sectional design using quantitative data collection approaches. A total of 150 nurses were sampled with a response rate of 95%. Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 23. The analysis included logistic regression to predict factors associated with nurses’ knowledge and attitude in caring for elderly patients, after multicollinearity diagnosis and controlling the effect of confounding variables. Results Majority (83.8%) of the nurses demonstrated good knowledge of the aging process, knowledge in the care of the elderly (88.7%), and (84.5%) had a positive caring attitude towards the elderly. Professional education, professional qualification, and knowledge on aged care were significantly associated with nurses’ attitude towards the elderly (p Conclusion The majority of nurses demonstrated good knowledge and attitude in the aging process and care of the aged. Lack of special wards/facilities and lack of staff motivation were the leading perceived barriers to rendering care to the elderly. Scaling up gerontological nursing programs and establishing special aged care facilities in Ghana with appropriate policy guidelines and regulations for implementation of care will help improve nurses’ knowledge and caring attitudes toward the care of elderly patients. Likewise, a national geriatric care policy would help consolidate standard geriatric care in Ghana.