Objective To investigate the cognitive frailty in elderly population with comorbidity in the Department of General Medicine and to evaluate its influencing factors. Methods A retrospective analysis was conducted of the clinical data of 206 elderly patients with comorbidity admitted to the Department of General Medicine of Dongguan People′s Hospital from January 2023 to December 2024. According to the diagnostic criteria for cognitive frailty proposed by the International Academy of Nutrition and Aging, the 206 elderly patients were divided into a cognitive frailty group (n=69) and a non-cognitive frailty group (n=137). The types of chronic diseases, comorbidity severity [age-adjusted Charlson comorbidity index (aCCI)], and serum homocysteine (Hcy) on the day after admission were compared between the two groups. SPSS 25.0 was used for data analysis, and t test or Chi-square test was used for comparison between groups according to the data type. Multivariate logistic regression analysis was used to evaluate the influencing factors of cognitive frailty in elderly patients with comorbidity. Results Among the 206 elderly patients with comorbidity in the Department of General Medicine, heart diseases were the most common chronic disease (56.80%), followed by hypertension (38.35%) and cerebrovascular disease (21.36%), and asthma was the least common (0.97%). The incidence of cognitive frailty was 33.50% (69/206). The proportion of cerebrovascular disease, aCCI scores, proportion of poor self-efficacy of chronic disease management, proportion of poor nutritional status, and serum Hcy levels on the day after admission in the cognitive frailty group were significantly higher than those in the non-cognitive frailty group, with statistically significant differences (P<0.05). Multivariate logistic regression analysis showed that cerebrovascular disease (OR=2.683,95%CI 1.409-5.111; P<0.05), aCCI score (OR=4.272,95%CI 2.516-7.253; P<0.05), poor self-efficacy of chronic disease management (OR=2.872,95%CI 1.606-5.136; P<0.05), poor nutritional status (OR=2.705,95%CI 1.442-5.072; P<0.05), and serum Hcy on the day after admission (OR=3.225,95%CI 1.835-5.667; P<0.05) were all risk factors of cognitive frailty in elderly patients with comorbidity in the Department of General Medicine. Conclusion Cognitive frailty in elderly patients with comorbidity in the Department of General Medicine is affected by chronic disease types, comorbidity severity, poor nutritional status, serum Hcy levels on the day after admission, and self-efficacy of chronic disease management. In clinical practice, special attention should be paid to elderly patients with comorbidity who have the aforementioned high-risk factors.