<p>The aim of this research is to enhance therapeutic outcomes in children diagnosed with severe craniocerebral trauma by evaluating the contributing factors involved in cerebral injury. The investigation focused on evaluating the impact of infusion therapy on the improvement of pediatric patients’ conditions with SCCT, particularly by assessing hydrobalance indicators. Adaptive changes associated with the humoral stress response were evaluated through alterations in hormone concentrations (thyrotropin (TSH), cortisol (C), prolactin (P)). Concentrations of plasma protein and glucose were analyzed. A total of 804 children with isolated severe craniocerebral trauma (SCCT) were enrolled and stratified into retrospective (<i>n</i> = 474) and prospective (<i>n</i> = 100) cohorts. Children with negative hydrobalance exhibited a higher mortality rate compared to those with positive hydrobalance (24% vs. 10%, <i>p</i> ≤ 0.05). Positive hydrobalance, in conjunction with appropriate infusion therapy and rehydration, positively influenced the prognosis of severe cranio-cerebral trauma (SCCT). These findings can be applied in clinical practice to optimize the treatment of children with SCCT and improve their prognosis. The level of total protein was higher in conscious children after 48&#xa0;h (59.9 ± 1.5&#xa0;g/L, <i>p</i> ≤ 0.05) in comparison to deceased individuals (54.9 ± 1.6&#xa0;g/L, <i>p</i> ≤ 0.05). Stress-induced hyperglycemia was associated with the severity of severe cranio-cerebral trauma. The study corroborated the significance of infusion therapy in the treatment of children with SCCT. Indicators of total protein, glucose, and P concentrations can serve as valuable tools for assessing the severity and prognostication of SCCT.</p>