Background: Diabetes distress and depression are known barriers to medication adherence in patients with type 2 diabetes. Limited research has explored this relationship in patients treated at Egyptian family health facilities. Objectives: To assess the association of diabetes distress and depressive symptoms with medication adherence among people with type 2 diabetes attending family medicine units/centers in Port Said City. Patients and Methods: A cross-sectional analytic study included 370 diabetic patients from 5 family health facilities in Port Said City, used convenient sampling. Data were collected using a semi-structured questionnaire, including demographic, disease profiles, the Diabetes Distress Scale (DDS-17), the Patient Health Questionnaire (PHQ-9), the General Medication Adherence Scale (GMAS), and recent HbA1c results. Results: Suboptimal medication adherence (77.03%), depressive symptoms (28.38%), and diabetes distress (35.41%) were prevalent among the participants. Multiple logistic regression analysis revealed that predictors of optimal medication adherence included female gender (OR 2.470, P=0.013), sufficient income (OR 4.703, P<0.001), absence of dyslipidemia (OR 0.273, P=0.002), and absence of depressive symptoms (OR 0.197, P=0.003). Diabetes distress was clinically associated with suboptimal medication adherence, but this association was not statistically significant. Conclusion: Depressive symptoms were associated with suboptimal medication adherence. While diabetes distress showed a clinical link to suboptimal adherence, it was not statistically significant. These findings emphasize the importance of addressing depressive symptoms and monitoring diabetes distress in clinical practice to improve medication adherence.