CDKL5 Deficiency Disorder (CDD) is a rare disease that presents as a set of neurological deficits including early-life epilepsy, intellectual disability, and autistic-like behaviors. It results from pathogenic mutations in the gene for cyclin-dependent kinase-like 5 (CDKL5), a protein that is highly expressed in brain. There is no cure for CDD and seizures in this disorder are typically resistant to traditional anti-epileptic drugs, although some patients respond well to cannabidiol. However, underlying mechanisms of what causes hyperexcitability and neurological deficits in CDD is poorly understood. We investigated the novel Cdkl5R59X mouse (R59X), and observed that mutant mice have social interaction and memory deficits, and decreased latency to seizure after administration of pentylenetetrazol. Given the observed behavioral alterations and hyperexcitability in R59X mice, we hypothesized that mutant mice would exhibit underlying molecular and functional alterations in proteins involved in regulating the E:I balance. Indeed, we observed a specific decrease in membrane-bound AMPA receptor (AMPAR) subunit GluA2 as well as decreased GluA2:GluA1 in the hippocampus of R59X mice, suggesting an increase in hippocampal GluA2-lacking AMPARs, which are calcium permeable and have significant roles in regulating neuronal plasticity and excitability. Indeed, decreased hippocampal GluA2 was accompanied by inward rectification of AMPAR currents in whole-cell patch recordings from hippocampal CA1 neurons, indicative of an increased population of functional GluA2-lacking AMPARs, and elevated early-phase long-term potentiation at Schaffer collateral-CA1 synapses. Finally, we evaluated the therapeutic potential of GluA2-lacking AMPAR blocker IEM-1460 as well as cannabidiol to observe 1) whether blocking increased hippocampal GluA2-lacking AMPARs would attenuate behavioral alterations and hyperexcitability in R59X mice and 2) whether cannabidiol shows therapeutic efficacy in R59X mice similar to human CDD patients, thus validating R59X mice as a relevant model to test potential therapeutics in CDD. Indeed, IEM-1460 significantly rescued deficits in social behavior, short-term memory, and latency to seizure while cannabidiol significantly rescued deficits in short and long-term memory and latency to seizure. These results verify that blocking increased GluA2-lacking AMPARs may be a successful therapeutic strategy in CDD, and that both IEM-1460 and cannabidiol may attenuate hyperexcitability as well as autistic-like behaviors and memory deficits in CDD.