Background: Arterial cannulation and intra-arterial (IA) fluid and blood resuscitation in the patients with severe shock is an easier approach compared with the intravenous (IV) access if concerns regarding the efficiency and safety of this approach are addressed. Objectives: We hypothesized that IA fluid resuscitation is more effective than IV resuscitation in restoring cardiac contractions (CC) of cardiac-arrested mice following severe hemorrhagic shock. Methods: Mice (N = 22) were anesthetized using ketamine/xylazine. Arterial and venous systems accessed through cannulation of the carotid artery and the Jugular vein, respectively. As much blood as possible was aspirated from the carotid artery access. Mice were observed until the complete cessation of chest wall motions. Following 30 seconds delay, IV (N = 5) and IA access (N = 6) were used for fluid resuscitation using Ringer Lactate (RL) in a similar volume to the aspirated blood. Mice were observed for restoration of chest wall motions. In phase-IIof the study, after cessation of chest motions, mice (N = 11) underwent a thoracotomy and CCs were observed. In three mice, IV RL Infusion after cardiac arrest failed to restore CCs and was followed by IA RL infusion. In eight mice, following cardiac arrest intermittent IA RL infusion was performed. Results: While IV RL Infusion failed to restore chestmotion inmice (N = 5), IA RL infusion restored chestmotion in allmice examined (N = 6) (P = 0.0067). In three mice, IV RL infusion after cardiac arrest showed no effect on CC. After failure of venous infusion, IA RL infusion was performed which resulted in restoration of CC for 13.33 ± 1.76 minutes. In eight mice, intermittent IA infusion of RL after cardiac arrest, sustained CC for 31.43 ± 10.9 minutes (P = 0.017). Conclusions: IA fluid resuscitation is superior to IV resuscitation in hemorrhagic shock induced cardiac arrest.