Objectives <p>The effect of the duration of medication with metformin and sulfonylurea (SUs) on microvascular complications based on the duration of type 2 diabetes (DM2) is unclear. The aim of this study was to investigate the association of medication time with metformin and SUs and microvascular complications in newly diagnosed DM2 patients.</p> Methods <p>In this prospective multi-cohort study, data from 3,904 newly diagnosed DM from three cohorts of the Tehran Lipid and Glucose Study (TLGS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Atherosclerosis Risk in Communities (ARIC) with a mean age of 59.6 ± 08 years were pooled. Metformin medication time alone, SUs alone, and a combination of both since drug initiation were defined as exposure. The incidence of microvascular complications (diabetic nephropathy or retinopathy) was defined as outcomes. The cumulative exposure to metformin, SUs, aspirin, statin, and anti-hypertensive medication was also determined using the same approach.</p> Results <p>Metformin alone, SUs alone, and the combination of both reduced the hazard of microvascular complications by 8%(HR_Adj: 0.92, 95% CI: 0.89, 0.96, P: 0.001), 6%(HR_Adj: 0.94, 95% CI: 0.92, 0.97, P: 0.004), and 9%(HR_Adj: 0.91, 95% CI: 0.89, 0.94, P: 0.001) for each year of use, respectively (<i>p</i> &lt; 0.05). The protective effect of metformin and SUs, individually or in combination, on microvascular complications started approximately five years after the initial treatment and continued until approximately 15 years after the initial treatment and then reached a plato.</p> Conclusion <p>long-term use of metformin and SUs individually and in combination was associated with a decrease in the risk of microvascular outcomes in newly diagnosed DM for up to about one decade. These findings highlight the importance of choosing an appropriate treatment regimen for new patients with type 2 diabetes. Appropriate oral therapy can minimize microvascular complications and improve overall well-being.</p>