Objective This study aimed to explore the effect of different administration routes of a low dose of tirofiban on acute ischemic stroke (AIS) patients with successful recanalization after endovascular treatment (EVT). Methods This is a cohort study that retrospectively analyzed data of patients with AIS who underwent EVT and achieved successful recanalization from a prospective registry. Eligible patients were divided into three groups according to their use of tirofiban. Propensity score matching (PSM) was used to balance baseline bias. Safety outcomes included any intracranial hemorrhage (ICH) and symptomatic ICH (sICH). Efficacy outcomes included arterial reocclusion, in-hospital mortality, 3-month mortality, and 3-month functional outcomes. Results We included 821 patients with 306 in the no tirofiban group, 202 in the IA + IV tirofiban group, and 313 in the IV tirofiban group. After PSM, each group included 101 patients with balanced baseline characteristics. There was no difference between the IV tirofiban group and the no tirofiban group in terms of safety and efficacy outcomes (all p > 0.05). Compared with no tirofiban, IA + IV tirofiban group did not increase ICH (30.7% vs. 37.6%, p > 0.05) and sICH (6.9% vs. 17.8%, p > 0.05) whereas reduced 3-month mortality (14.3% vs. 28.7%, p < 0.05) and improved 3-month modified Rankin Scale (median 3 vs. 4, p < 0.05). Conclusions A low dose of tirofiban, regardless of their administration routes, was safe for AIS patients who achieved successful recanalization with EVT, whereas only IA + IV tirofiban improved clinical outcomes.