Rats of OXYS strain are characterized by genetically defined accelerated senescence. Ceftriaxone (CEF) exerts neuroprotective effects by decreasing the excitotoxicity and activation of antioxidant system. Here, we studied the effects of CEF (50 or 100 mg/kg/day, i.p., 36 days) on cognitive and neuronal deficits in 5-month-old OXYS rats. Chronic CEF administration in a dose of 100 mg/kg partially inhibited impairments of movement and restored the deficit in the novel object recognition in OXYS rats. Neuromorphologically, control OXYS rats exhibited a lowered neuronal density in the hippocampal CA1 area and there was a tendency to decrease in the substantia nigra pars compacta compared to Wistar controls. Both doses of CEF increased the density of pyramidal neurons in the CA1 area in OXYS rats. Control OXYS rats demonstrated a tendency to lower tyrosine hydroxylase (TH) immunoreactivity in the striatum compared with Wistar rats, while CEF treatment at a dose of 50 mg/kg significantly augmented this parameter. In control OXYS rats, the levels of neurogenesis in the subgranular zone of the dentate gyrus of the hippocampus were significantly higher than in Wistar rats indicating compensatory processes that probably prevented the further induction of neurogenesis by CEF. Restoration of the recognition function and neuronal density in the CA1 area in OXYS rats after CEF treatment might be related to activation of the mechanisms that provide survival of newborn and mature neurons. The data suggested CEF as a promising pharmacological tool for the prevention of cognitive decline at accelerated aging.