Injury to the central nervous system (CNS) initiates a series of complex events that are responsible for cell and tissue damage over time. The primary insult, i.e., trauma, ischemia, hypoxia, hyperthermia, etc., results in secondary injury cascades involving release of several neurochemicals and other factors that alters the brain micro-fluid environment. The most important secondary injury events include increased levels of cytokines, e.g., Tumor Necrosis Factor-alpha (TNF-α), and production of nitric oxide (NO) causing direct damages to cell membranes, disrupting the blood-brain barrier (BBB) function and brain edema formation. Apart from these factors, several other neurochemical mediators of the BBB and brain edema formation, i.e., serotonin, prostaglandin, histamine, glutamate, dynorphin, etc., contribute to cell and tissue injuries. Importantly, an interaction among these mediators plays prominent roles in the development of brain pathology. It appears that some of the endogenously released substances have neuroprotective ability, whereas the other elements are injurious to the CNS indicating that a balance between endogenous neurodestructive and neuroprotective factors is crucial for the cell injury or survival. Thus, using highly selective and specific antibodies raised against possible neurodestructive elements is likely to neutralize their effects in vivo and results in neuroprotection. This review deals with neuroprotective effects of antibodies directed against serotonin, dynorphin, TNF-α and nitric oxide synthase in animal models of CNS trauma and hyperthermic brain injury. Studies carried out in our laboratory since last 2 decades show that topical or intracerebroventriculalry administered antibodies against neurodestructive factors attenuate trauma or hyperthermia induced BBB dysfunction, brain edema formation and cell damage. These novel observations indicate a promising role of antibodies as therapy in CNS injuries to induce neuroprotection. The possible mechanisms and functional significance of antibodies induced neuroprotection is discussed.