The purpose of the present study was to investigate the effects of ERK1/2 inhibition on both the amygdala and hippocampal structures, and to investigate its role in regulating memory for sexual information. This study utilized a cerebral ischemia reperfusion (IR) model to produce a stressful brain condition that highlights the possible involvement of a hippocampal GC/pERK1/2/BDNF pathway in the resulting sexual consequences of this ailment. Male Wistar rats were divided into four groups: (1) sham; (2) IR: subjected to 45 min of ischemia followed by 48 h of reperfusion; (3) PD98059: received PD98059 at 0.3 mg/kg, i.p.; (4) IR + PD98059. This study provides new evidence for cerebral IR-induced amygdala injury and the sexual impairments that are associated with motor and cognitive deficits in rats. These findings were correlated with histopathological changes that are defined by extensive neuronal loss in both the hippocampus and the amygdala. The current study postulated that the ERK inhibitor PD98059 could reverse IR-induced injury in the amygdala as well as reversing IR-induced sexual impairments. This hypothesis is supported by the ability of PD98059 to: (1) restore luteinizing hormone and testosterone levels; (2) increase sexual arousal and copulatory performance (as evidenced by modulating mount, intromission, ejaculation latencies, and post-ejaculatory intervals); (3) improve the histological profile in the amygdala that is associated with reduced glutamate levels, c-Fos expression, and elevated gamma aminobutyric acid levels. In conclusion, the present findings introduce pERK1/2 inhibition as a possible strategy for enhancing sexual activity in survivors of IR.