Epilepsy is a complicated neurological disorder that occurs worldwide and features several kinds of comorbidities in addition to recurrent seizures. One of the most common comorbidities is cognitive impairment, which seriously affects patients' quality of life. Through activating pre- and postsynaptic adenosine A1 receptors (A1Rs), adenosine has demonstrated anticonvulsant and neuroprotective effects in many epileptic animal models. However, whether the neuroprotective effect of A1Rs will protect cognition during epileptogenesis remains unknown. Therefore, by using A1R knockout (KO) mice and establishing a pentylenetetrazole (PTZ)-kindled model of epilepsy, the present study investigated A1Rs' influences on memory and synaptic function. Morris water maze test results indicated that A1R knockout exacerbated the memory impairment induced by PTZ kindling compared with the wild-type group. To further study the synaptic function of epileptic A1Rs KO mice, we recorded long-term potentiation (LTP) in the hippocampal CA3-CA1 pathway, and LTP was highly inhibited in kindled A1R KO mice compared with kindled wild-type mice. To reveal the mechanisms underlying these effects, neuronal loss, cell apoptosis, and relevant synaptic protein levels in hippocampus were assessed. Epileptic A1R KO mice exhibited significant reductions in neuronal cell survival in the CA1 region and a marked increase in the activation of caspase-3 in the hippocampus compared with epileptic wild-type mice. In addition, an obvious decrease in the PSD95 and BDNF expression levels of epileptic A1R KO mice was observed 7 days after complete kindling. In conclusion, these findings indicated that A1Rs play an important protective role against cognitive impairment by reducing neuron loss and increasing BDNF and PSD95 levels. Activation of A1Rs during epileptogenesis might be beneficial to the preservation of epileptic individuals' cognitive functions.