Management of pain in research swine used for studies involving painful procedures is a considerable challenge. Here we assessed whether a regional anesthesia method is effective for pain control of hindlimb injuries in pigs used for research in bone fracture healing. For this randomized controlled study, we administered regional anesthesia before an experimental femoral injury was produced. Using ultrasound guidance, we placed sterile infusion catheters near the sciatic and femoral nerves and administered local anesthetic (bupivacaine) for the first 24 h after surgery. We evaluated various behavioral and physiologic parameters to test the hypothesis that this regional anesthesia would provide superior analgesia compared with systemic analgesia alone. We also collected blood samples to evaluate serum levels of cortisol and fentanyl postoperatively. At the end of the study period, we collected sciatic and femoral nerves and surrounding soft tissues for histopathologic evaluation. Treatment pigs had lower subjective pain scores than did control animals. Control pigs had a longer time to first feed consumption and required additional analgesia earlier in the postoperative period than did treatment pigs. Ultrasound-guided regional anesthesia is a viable and effective adjunct to systemic analgesics for providing pain control in swine with experimental femoral fractures.