This study evaluates compositions of tantalum-containing mesoporous bioactive glass (Ta-MBG) powders using a porcine fatal liver injury model. The powders based on (80-x)SiO2-15CaO-5P2O5-xTa2O5 compositions with x = 0 (0Ta/Ta-free), 1 (1Ta), and 5 (5Ta) mol% were made using a sol–gel process. A class IV hemorrhage condition was simulated on the animals; hemodynamic data and biochemical analysis confirmed the life-threatening condition. Ta-MBGs were able to stop the bleeding within 10 min of their application while the bleeds in the absence of any intervention or in the presence of a commercial agent, AristaTM (Bard Davol Inc., Rhode Island, USA) continued for up to 45 min. Scanning electron microscopy (SEM) imaging of the blood clots showed that the presence of Ta-MBGs did not affect clot morphology. Rather, the connections seen between fibrin fibers of the blood clot and Ta-MBG powders point towards the powders’ surfaces embracing fibrin. Histopathological analysis of the liver tissue showed 5Ta as the only composition reducing parenchymal hemorrhage and necrosis extent of the tissue after their application. Additionally, 5Ta was also able to form an adherent clot in worst-case scenario bleeding where no adherent clot was seen before the powder was applied. In vivo results from the present study agree with in vitro results of the previous study that 5Ta was the best Ta-MBG composition for hemostatic purposes.