Acute compartment syndrome (ACS) is a devastating complication that can happen in almost every part of the human body, most noticeably after long bone fractures. The cardinal symptom of ACS is pain in excess of what would otherwise be expected from the underlying injury and unresponsive to routine analgesia treatment. There is paucity of literature on major analgesic management strategies including opioid analgesia, epidural anesthesia, and peripheral nerve blocks with regard to their differential efficacy and safety of pain management in patients at risk of developing ACS. The lack of quality data has led to recommendations that are perhaps more conservative than they should be, particularly when it comes to peripheral nerve blocks. In this review article, we attempt to make recommendations in favor of regional anesthesia in this vulnerable group of patients and strategies that will optimize adequate pain control and improve surgical outcome without jeopardizing patient safety.