Background: Having depression and living in a rural environment have separately been associated with poor diabetes outcomes, but there little is known about the interaction between the 2 risk factors. This study investigates the association of depression and rurality with glycemic control in adults, as well as their interaction. Methods: This is a repeated cross-sectional study with data collected from 2010 to 2017 (n = 1,697,173 patient-year observations), comprising a near-complete census of patients with diabetes in Minnesota. The outcome of interest was glycemic control defined as hemoglobin A1c under 8%. We used a logit model with clinic-level random effects to predict glycemic control as a function of depression, patient rurality, and their interaction, adjusted for differences in observed characteristics of the patient, clinic, and patient's neighborhood. Results: Having depression was associated with lower probability of achieving glycemic control (P < .001). Although rurality alone had no association with glycemic control, significant interactions existed between depression and rurality. Living in a small rural town mitigated the negative association between depression and glycemic control (P < .001). Conclusion: Although patients with depression had poorer glycemic control, living in a small rural town reduced the negative association between depression and glycemic control. (J Am Board Fam Med 2020;33:913-922.