Background: Major depressive disorder (MDD) is a major mood disorder characterized by chronic low mood with cognitive impairment. Diabetes mellitus is a group of chronic metabolic diseases, Type 2 diabetes (T2DM) will obviously increase the risk of dementia. People with the the comorbidity of T2DM and MDD have a higher risk of dementia. In this study, we aim to investigate partial cognitive impairment in the comorbidity of T2DM and MDD, and to determine the relationship between changes in caspase-1 expression and cognitive impairment. To further explore the role of caspase-1 in the partial cognitive impairment in the comorbidity of T2DM and MDD. Methods: A total of 162 people were enrolled, there were 49 patients in the comorbidity of T2DM and MDD group, 54 patients in the MDD group, and 45 patients in the T2DM group. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess the cognitive function of these three groups. Serum level of caspase-1 was determined by ELISA, and the level of caspase-1, as well as partial cognitive function, was compared in the three groups. Results: The cognitive impairment of patients of the comorbidity of T2DM and MDD group was worse than the MDD group and the T2DM group, and the immediate memory, attention, and delayed memory in the comorbidity of T2DM and MDD group were lower than those in the other two groups, and the caspase-1 of the comorbidity of T2DM and MDD is higher than the caspase-1 of the MDD group, all the difference was statistically significant (P < 0.05). Caspase-1 protein was negatively correlated with immediate memory, attention, and delayed memory (r=-0.332, r=-0.182, r=-0.313, P<0.05). Conclusion: The cognitive impairment of patients of the comorbidity of T2DM and MDD group was worse than the MDD group and the T2DM group, and the immediate memory, attention, and delayed memory in the comorbidity of T2DM and MDD group were lower than those in the other two groups. The differences of the caspase-1 in the comorbidity of T2DM and MDD group, the MDD group and the T2DM group were significant, the level of the caspase-1 is higher than the other two groups, the cognitive impairment of three groups is associated with caspase-1, suggesting caspase-1 protein may be involved in the cognitive impairment aggravation mechanism of the comorbidity of T2DM and MDD group.