The significance of health literacy for elderly individuals with chronic illnesses lies in managing and delaying disease development, which is affected by personal and environmental factors. Family communication can provide an emotional support environment; self-efficacy is an important factor of subjective initiative and personality. A relatively persistent thinking and behavior pattern can affect the environment, subjective initiative, and individual health outcomes. This study aims to explore the effects of the Big Five personality traits on the health literacy of elderly individuals with chronic illnesses and to hypothesize that family communication and self-efficacy mediate the Big Five personalities and health literacy. A cross-sectional study of 2251 elderly individuals with chronic diseases was conducted through nationwide random quota sampling. The structural equation model was used to explore the mediating role of family communication and self-efficacy between the Big Five personality and health literacy. Family communication played a simple mediating role in the influence of extraversion, agreeableness, conscientiousness, and neuroticism on health literacy. Self-efficacy played a simple mediating role in the influence of the Big Five personalities on health literacy. Self-efficacy and family communication played a chain mediating role between extraversion, agreeableness, conscientiousness, neuroticism, and health literacy. Nurses can enhance the health literacy of elderly individuals with chronic illnesses with extraversion, agreeableness, conscientiousness, and neuroticism through family communication and self-efficacy while promoting the health literacy of those with openness through self-efficacy.