Population aging is one of the major challenges facing modern society and has attracted global attention. With population aging becoming a global phenomenon, the impact of age-related diseases on health is increasing rapidly. Frailty is one of the most pressing issues facing older adults. The purpose of this study was to explore the interrelationship between health literacy, social support, depression, and frailty among older patients with hypertension and diabetes in China. No studies have investigated the mediating effects of social support and depression between health literacy and frailty. The findings of this study can be applied to help ameliorate frailty in older hypertensive and diabetic patients. Data were collected from 637 older hypertensive and diabetic patients aged 65 years and older in Sichuan Province, China. We used structural equation modeling (SEM) to test the hypothesized relationship among the variables. The results showed that 42.4% of the participants suffered from frailty. The mean scores for health literacy, social support, depression, and frailty were 13.6 ± 5.7, 35.7 ± 6.5, 4.0 ± 3.4, and 3.5 ± 2.1, respectively. Social support had a direct negative association with frailty (β = −0.128, 95%CI: [−0.198, −0.056]), and depression had a direct positive association with frailty (β = 0.326, 95%CI: [0.229, 0.411]), while social support had no direct association with depression. Health literacy had a direct positive association with social support (β = 0.151, 95%CI: [0.077, 0.224]) and a direct negative association with depression (β = −0.173, 95%CI: [−0.246, −0.1]), while health literacy had an indirect negative association with frailty through the mediating effect of social support and depression. To mitigate frailty in older patients with hypertension and diabetes, measures that provide social support, and enhance health literacy, while alleviating depression, should be considered, along with greater attention to patients who are divorced, widowed, or unmarried, those with comorbidities, and those with lower socioeconomic status.