The aim of the study was to study the prospects of histaminergic and imidozolinergic drugs for thetreatment of acute period of traumatic brain injury. Material and methods. The study was performed on 182 mongrel mice with a body weight of 20-26 g who had suffered a traumatic brain contact injury (TBI). TBI was applied using the modified Allen method under nembutal anesthesia. The skull and brain bones were damaged symmetrically on both sides. To determine the anti-ischemic activity of drugs, a decapitation model of complete cerebral ischemia (gasping) was used. The antihypoxic activity of substances was determined by the duration of the reserve time in mice under conditions of normobaric, progressive hypoxia with hypercapnia, Changes in the functioning of compensatory mechanisms of the brain were studied by determining the rate of production of active avoidance reactions. The drugs were administered intravenously for 6 or 9 days of the acute period in the following dosages: betaserk 16 and 24 mg / kg, moxonidine 0.2 and 0.4 mg / kg, diphenhydramine 50 mg/ kg. The reliability of the differences (control-experience) was assessed according to the Student's criterion (t) and the Mann–Whitney criterion (U).Results. Unlike diphenhydramine, an antagonist of H1-histamine receptors, betaserk, an antagonist of H3-histamine receptors, and moxonidine, an agonist of I1-imidazoline receptors have a favorable anti-ischemic effect in the acute period of traumatic brain injury. Against the background of the administration of drugs, starting from 2 days after TBI, a favorable therapeutic effect was found when prescribing betaserk at a dose of 16 and 24 mg / kg. The drug increases the duration of gasping by 42%-73% (P < 0.05). The effect of moxonidine was less significant (29-34%) (P<0.05), and diphenhydramine showed no pronounced protective effect. The administration of drugs for 9 days showed that moxonidine increases the resistance of injured mice to hypoxic stress by 18.4% (P< 0.05), betaserk – by 13.9%, and diphenhydramine reduces it by 13%. Betaserk additionally activates the production of simple adaptive responses In animals, there was a 51% decrease in the number of samples spent on the production of URAI, and a 16% reduction in training time (P<0.05). On the contrary, moxonidine slows down the process of developing a simple adaptive response.Сonclusion. The study obtained evidence of neuroprotective properties of histaminergic and imidozolinergic drugs.