Objectives People with diabetes are at high risk of polypharmacy owing to complex treatment of diabetes and comorbidities. Polypharmacy is associated with increased risk of adverse reactions and decreased compliance. Therefore, the objectives of this study were to assess polypharmacy in people with type 2 diabetes (T2D) and associated diabetes-related factors in rural areas in Vietnam. Method People with T2D (n = 806) who had received treatment for diabetes at a district hospital were invited to participate in a questionnaire-based cross-sectional survey. Polypharmacy was defined as ≥5 types of medicine and assessed as a) prescription medicine and non-prescription/over the counter (OTC) medicine and b) prescription medicine and non-prescription/OTC, herbal and traditional medicine, and dietary supplement. Multiple logistic regression was used to investigate the association between polypharmacy and diabetes specific factors: duration, comorbidities and diabetes-related distress. Results Of the people with T2D, 7.8% had a medicine use corresponding to polypharmacy (prescription medicine and non-prescription/OTC), and 40.8% when herbal and traditional medicine, and dietary supplement were included. Mean number of medicine intake (all types of medicines and supplements) were 3.8±1.5. The odd ratios (ORs) of polypharmacy (medicine and supplements) increased with diabetes duration (<1–5 years OR = 1.66; 95%CI: 1.09–2.53 and >5 years OR = 1.74; 95%CI: 1.14–2.64 as compared to ≤1-year duration of diabetes), number of comorbidities (1–2 comorbidities: OR = 2.0; 95%CI: 1.18–3.42; ≥3 comorbidities: OR = 2.63;95%CI: 1.50–4.61 as compared to no comorbidities), and suffering from diabetes-related distress (OR = 1.49; 95%CI: 1.11–2.01) as compared to those without distress. Conclusions In rural northern Vietnam, persons with longer duration of T2D, higher number of comorbidities and diabetes-related stress have higher odds of having a medicine use corresponding to polypharmacy. A high proportion of people with T2D supplement their prescription, non-prescription/OTC medicine with herbal and traditional medicine and dietary supplements.