Intravenous thrombolytic therapy with alteplase (IVT) is a standard of care in ischemic stroke, while recent trials investigating direct endovascular thrombectomy (EVT) approaches showed conflicting results. Yet, the effect of IVT on secondary injury volumes in patients with complete recanalization has not been analyzed. We hypothesized that IVT is associated with worse functional outcome and aggravated secondary injury volumes when administered to patients who subsequently attained complete reperfusion after EVT. Anterior circulation ischemic stroke patients with complete reperfusion after thrombectomy defined as thrombolysis in cerebral infarctions (TICI) scale 3 after thrombectomy admitted between January 2013–January 2021 were analyzed. Primary endpoints were the proportion of patients with functional independence defined as modified Rankin Scale (mRS) score 0–2 at day 90, and secondary injury volumes: Edema volume in follow-up imaging measured using quantitative net water uptake (NWU), and the rate of symptomatic intracerebral hemorrhage (sICH). A total of 219 patients were included and 128 (58%) patients received bridging IVT before thrombectomy. The proportion of patients with functional independence was 28% for patients with bridging IVT, and 34% for patients with direct thrombectomy (p = 0.35). The rate of sICH was significantly higher after bridging IVT (20% versus 7.7%, p = 0.01). Multivariable logistic and linear regression analysis confirmed the independent association of bridging IVT with sICH (aOR: 2.78, 95% CI: 1.02–7.56, p = 0.046), and edema volume (aOR: 8.70, 95% CI: 2.57–14.85, p = 0.006). Bridging IVT was associated with increased edema volume and risk for sICH as secondary injury volumes. The results of this study encourage direct EVT approaches, particularly in patients with higher likelihood of successful EVT.