Background/ Introduction: Epigenetic mechanisms control brain development. Such mechanisms include DNA methylation with key roles in neuronal maturation. Methyl CpG Binding Protein (MeCP2) is the main protein that binds the methylated DNA in the brain. Mutations in the MECP2 gene cause changes in neuronal structure and problems in normal brain functioning. This leads to development of an X-linked disease called Rett Syndrome (RTT) in which neurite formation and neuronal maturation are impaired. MeCP2 has two protein isoforms: MeCP2E1 and MeCP2E2, with exceptionally abundant expression in the brain. Among MeCP2 protein mutations, the R255X (nonsense mutation) is a common mutation that is recognized to be the 3rd most common RTT-associated mutation, located in the MeCP2 transcription repression domain. Rationale and hypothesis: RTT predominantly affects female patients; however, most of the pre-clinical studies have been done on male mice. At present, there is no cure for RTT, and the underlying mechanism of the disease is still not fully understood. Recently, RTT has been categorized as a neurometabolic disorder and a major metabolic pathway that is disturbed in RTT patients and mouse models is glucose metabolism. A commonly used anti-diabetic drug called “metformin” targets gluconeogenesis. Therefore, I hypothesize that administration of metformin in vivo improves RTT-associated symptoms and molecular deficits in R255X RTT mice. Methodology: The wild type (WT) and mutant R255X RTT male and female mice were divided into 3 groups: sham (no treatment), vehicle control, and metformin treatment. Drug delivery was done through daily IP injections and over a period of 3 weeks. Mice were monitored for different phenotypic criteria at the end of the treatments. Results and Conclusion: Mutant R255X mice exhibit altered body weight, phenotypic deficits and behavioral abnormalities, including change in anxiety, consistent with previous research. Metformin treatment alleviated several phenotypic symptoms in a dose-dependent manner. Anther impacted characteristic was social behavior. Metformin has been an emerging new drug to be considered for improving RTT associated symptoms. Our data may have significant importance for future therapeutic strategies for RTT.