Background We aimed to evaluate the age‐dependent effect of ticagrelor monotherapy after 3‐month dual‐antiplatelet therapy (DAPT) versus ticagrelor‐based 12‐month DAPT on major bleeding and cardiovascular events in patients with acute coronary syndrome. Methods and Results From the TICO trial (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus‐eluting Stent for Acute Coronary Syndrome), which randomized 3056 patients (median age, 61 years) to the ticagrelor monotherapy after 3‐month DAPT group or ticagrelor‐based 12‐month DAPT group, this post hoc analysis evaluated the age‐dependent effect of the treatment strategies on the primary end point (a composite of major bleeding, death, myocardial infarction, stent thrombosis, stroke, or target‐vessel revascularization) using the subpopulation treatment effect pattern plot. The cutoff age for distinguishing patients with greater benefit from this strategy was also determined. The risk reduction effect of ticagrelor monotherapy after 3‐month DAPT versus ticagrelor‐based 12‐month DAPT on the primary end point gradually increased with age and was more marked from the subpopulation of age 64 years with the change point. With this cutoff value of 64 years, the occurrence of the primary end point was significantly lower in the ticagrelor monotherapy after 3‐month DAPT group than in the ticagrelor‐based 12‐month DAPT group (4.4% versus 9.0%; P =0.002) in patients aged ≥64 years (n=1278), but it was not different in those aged <64 years (n=1778) with a significant interaction ( P ‐interaction=0.036). Conclusions The age‐dependent increase in the benefit of ticagrelor monotherapy after 3‐month DAPT versus ticagrelor‐based 12‐month DAPT was observed in the patients with acute coronary syndrome. In elderly patients with acute coronary syndrome, ticagrelor monotherapy after short‐term DAPT might be more optimal than ticagrelor‐based 12‐month DAPT.