Abstract Background The effects of cardiometabolic drugs on the prognosis of diabetic patients with COVID-19, especially very old patients, are not well known. This work was aimed to analyze the association between preadmission cardiometabolic therapy (antidiabetic, antiaggregant, antihypertensive, and lipid-lowering drugs) and in-hospital mortality among patients ≥80 years with type 2 diabetes mellitus (T2DM) hospitalized for COVID-19. Method We conducted a nationwide, multicenter, observational study in patients ≥80 years with T2DM hospitalized for COVID-19 between March 1 and May 29, 2020. The primary outcome measure was in-hospital mortality. A multivariate logistic regression analysis was performed to assess the association between preadmission cardiometabolic therapy and in-hospital mortality. Results Of the 2 763 patients ≥80 years old hospitalized due to COVID-19, 790 (28.6%) had T2DM. Of these patients, 385 (48.7%) died during admission. On the multivariate analysis, the use of dipeptidyl peptidase-4 inhibitors (adjusted odds ratio AOR 0.502, 95% confidence interval CI: 0.309–0.815, p = .005) and angiotensin receptor blockers (AOR 0.454, 95% CI: 0.274–0.759, p = .003) were independent protectors against in-hospital mortality, whereas the use of acetylsalicylic acid was associated with higher in-hospital mortality (AOR 1.761, 95% CI: 1.092–2.842, p = .020). Other antidiabetic drugs, angiotensin-converting enzyme inhibitors, and statins showed neutral association with in-hospital mortality. Conclusions We found important differences between cardiometabolic drugs and in-hospital mortality in older patients with T2DM hospitalized for COVID-19. Preadmission treatment with dipeptidyl peptidase-4 inhibitors and angiotensin receptor blockers could reduce in-hospital mortality; other antidiabetic drugs, angiotensin-converting enzyme inhibitors, and statins seem to have a neutral effect; and acetylsalicylic acid could be associated with excess mortality.