Studies suggest that repetitive injury synergy (RIS) can occur during a period of heightened vulnerability following concussion. For athletes, who are at greater risk for multiple concussions, understanding the mechanical injury mechanisms of repetitive mild traumatic brain injury (mTBI) is required for preventing the potentially devastating outcomes of multiple concussions. Although a single sub‐threshold mechanical stimulus will not cause cell death, it triggers a sub‐injurious biological response. We postulate that activated biochemical cascades from multiple injuries in succession are additive, becoming supra‐threshold for initiation of neurodegeneration and hypothesize that drugs, which target these cascades, can intervene to prevent their superposition. Organotypic hippocampal slice cultures subjected to 2 mechanical injuries (11.78 ± 0.44% equibiaxial strain, 20 s‐1 strain rate) 24 hours apart exhibited a significant and super‐additive increase in cell death in all regions of interest of the hippocampus 4 days following injury (n > 15, p < 0.05). A combination therapy of memantine and 17β‐estradiol was used to combat excitotoxicity and oxidative stress. Post‐injury treatment with the drug combination significantly reduced cell death (n > 25, p < 0.05). Our results suggest that therapeutic delivery following mTBI and subsequent mTBI exposure within 24 hours can prevent potential RIS in our model.