There has been renewed interest in decompressive craniectomy as a surgical treatment for elevated intracranial pressure (ICP), although evidence-based clinical data are still lacking and some experimental results are conflicting. Ongoing clinical trials on the use of this operation after traumatic brain injury (TBI) may clarify the clinical application of this technique, however, some pathophysiological issues, such as the timing of this operation, its effect on brain edema formation, and its role for secondary brain damage, are still controversial. This review addresses recent clinical data on the influence of decompressive craniectomy on the brain pathophysiology in TBI. Decompressive craniectomy with dural augmentation enlarges intracranial space so that the swollen cerebral hemisphere could expand out of normal cranial limits, avoiding progression of brain herniation. The gain in intracranial volume results in both the improvement of cerebral compliance and a decrease in ICP; the latter favors a rise in both cerebral blood flow and cerebral microvascular perfusion, which can be accompanied by elevation in brain tissue oxygen tension (PbtO2) as well as the return of abnormal metabolic parameters to normal values in cases of cerebral ischemia. Enhancement of edema formation, impairment of cerebrovascular pressure reactivity, and non-restoration of brain aerobic metabolism due to metabolic crisis may occur after craniectomy and require further investigations. This review suggests that decompressive craniectomy as the sole treatment is likely to be insufficient; efforts must be made to maintain adequate brain hemodynamics, preferably coupled with brain metabolism, in addition to treating brain metabolic abnormalities, during postoperative stages.