Open extremity fractures are high-risk injuries prone to significant complications, including soft tissue loss, bone defects, infection, infected nonunion, and the necessity for limb amputation. Large-scale multicenter prospective studies from the “Lower Extremity Assessment Project” (LEAP) and the “Major Extremity Trauma Consortium” (METRC) have provided novel scientific insights pertinent to the timeliness and appropriateness of specific treatment modalities aimed at improving outcomes of patients with open extremity injuries. These include the imperative for early administration of intravenous antibiotics within three hours of injury, preferably within one hour of hospital admission. Unlike the proven value of early antibiotics, the time to initial surgical débridement does not appear to affect infection rates and patient outcomes. Recent evidence-based consensus guidelines from the American Academy of Orthopaedic Surgeons (AAOS) provide scientific guidance for preventing surgical site infections in patients with open extremity fractures and support the decision-making of limb salvage versus amputation in critical open extremity injuries. Patient survival represents the overarching priority in the management of any trauma patient with associated orthopaedic injuries. Therefore, the timing and modality of managing open fractures must take into account the patient’s physiology, response to resuscitation, and overall injury burden. The present review was designed to provide a state-of-the-art overview on the recommended diagnostic workup and management strategies for patients with open extremity fractures, based on the current scientific evidence.